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Cognitive Dysfunction in Schizophrenia: Convergence of gamma-Aminobutyric Acid and Glutamate Alterations
Abstract
Impairments in certain cognitive functions mediated by the dorsolateral prefrontal cortex, such as working memory, are core features of schizophrenia. Convergent findings suggest that these disturbances are associated with alterations in markers of inhibitory gamma-aminobutyric acid and excitatory glutamate neurotransmission in the dorsolateral prefrontal cortex. Specifically, reduced gamma-aminobutyric acid synthesis is present in the subpopulation of gamma-aminobutyric acid neurons that express the calcium-binding protein parvalbumin. Despite presynaptic and postsynaptic compensatory responses, the resulting impaired inhibitory regulation of pyramidal neurons contributes to a reduction in the synchronized neuronal activity that is required for working memory function. Several lines of evidence suggest that these changes may be either secondary to or exacerbated by impaired signaling via the N-methyl-d-aspartate class of glutamate receptors. These findings suggest specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.
... Risks of psychosis correlate with higher striatal dopamine D2 receptor o pancy [21], further linking dopamine dysregulation and psychosis [22]. While gluta tergic deficits may provoke negative and cognitive symptoms of schizophrenia [23] disorder is likely linked to disrupted ontogenesis of the glutamatergic and GABAe neurons [24], and aberrant dorsolateral prefrontal cortex glutamatergic circuitry [25] ...
... Risks of psychosis correlate with higher striatal dopamine D2 receptor occupancy [21], further linking dopamine dysregulation and psychosis [22]. While glutamatergic deficits may provoke negative and cognitive symptoms of schizophrenia [23], the disorder is likely linked to disrupted ontogenesis of the glutamatergic and GABAergic neurons [24], and aberrant dorsolateral prefrontal cortex glutamatergic circuitry [25]. ...
Depression and schizophrenia are two highly prevalent and severely debilitating neuropsychiatric disorders. Both conventional antidepressant and antipsychotic pharmacotherapies are often inefficient clinically, causing multiple side effects and serious patient compliance problems. Collectively, this calls for the development of novel drug targets for treating depressed and schizophrenic patients. Here, we discuss recent translational advances, research tools and approaches, aiming to facilitate innovative drug discovery in this field. Providing a comprehensive overview of current antidepressants and antipsychotic drugs, we also outline potential novel molecular targets for treating depression and schizophrenia. We also critically evaluate multiple translational challenges and summarize various open questions, in order to foster further integrative cross-discipline research into antidepressant and antipsychotic drug development.
... Long-term stress, insomnia, and other mental factors affect the neuroendocrine system to produce a series of changes that eventually leads to the onset of fatigue (Kempke et al., 2015); 3) Compensation effects. When cognitive work is overloaded and efficiency decreases, the CNS inhibits negative feedback regulation to compensate for decreased work efficiency, which leads to fatigue (Lewis and Moghaddam, 2006); and 4) Imbalance in the excitation/inhibition pathway regulation. When there is an imbalance in the inhibition-excitation pathway in the CNS, fatigue occurs (Leavitt and Deluca, 2010). ...
... Glu and GABA are considered the major excitatory and inhibitory neurotransmitters in the CNS, respectively (Figure 10). Studies have identified the homeostatic mechanisms associated with cognitive and emotional functions (Lewis and Moghaddam, 2006). GABA synthesis in the brain relies on the conversion of Glu (Kuriyama and Sze, 1971), an excitatory neurotransmitter and raw material for the production of GABA, which is produced by the action of the Immunohistochemical staining for GABABR2 in the hippocampal CA3 region (×5, ×10, ×40 magnification) and the prefrontal cortex stromal layer (×10, ×40 magnification) of rats. ...
Background: Central fatigue (CF) is a subjective sense of tiredness associated with cognitive and memory disorders, accompanied by reduced physical endurance and negative emotions, such as anxiety and depression. Disease progression and prognosis with regards to CF have been unfavorable and possibly contribute to dementia, schizophrenia, and other diseases. Additionally, effective treatments for CF are lacking. KangPiLao decoction (KPLD) has been widely applied in clinical treatment and is composed of six Chinese herbal medicines, some of which have confirmed anti-fatigue effects. While glutamic acid (Glu) is the main excitatory transmitter in the central nervous system (CNS), gamma-aminobutyric acid (GABA) is the major inhibitory transmitter. Both are involved in emotional, cognitive, and memory functions. This research was designed to explore how KPLD regulates cognitive and emotional disorders in rats with CF and to identify the relationship between the regulatory effect and the GABA/Glu pathway.
Methods: The compounds comprising KPLD were analyzed using high-performance liquid chromatography-mass spectrometry. Sixty Wistar rats were randomly divided into six groups. The modified multiple platform method was used to induce CF. Cognitive, emotional, and fatigue states were evaluated by performing behavioral tests (Morris water maze [MWM], open-field test [OFT], and grip strength test). Histomorphology, western blotting, immunohistochemistry, and RT-qPCR were performed to investigate protein and mRNA expression levels in the hippocampus and prefrontal cortexes involved in the GABA/Glu pathway.
Results: Rats with CF exhibited impaired spatial cognition and increased negative emotions in the MWM and OFT. KPLD enabled the improvement of these symptoms, especially in the high-concentration group. Western blotting and RT-qPCR demonstrated that the expression of GABAARα1, GABAARγ2, GABABR1, and GAD67 in rats with CF was higher, whereas GAT-1 and NMDAR2B were lower in the hippocampus and prefrontal cortex. KPLD decreased the expression of GABAARα1, GABABR1, GABAARγ2, and GAD67 in the hippocampus and prefrontal cortex and enhanced the expression of NR2B in the prefrontal cortex.
Conclusion: KPLD significantly improved cognitive and emotional disorders in rats with CF by regulating the GABA/Glu pathway. Overall, KPLD may be a promising candidate for developing a drug for treating CF.
... Indeed, the primary axon of the CT neurons splits into two branches, one innervating TRN neurons, the other TC neurons (Bourassa et al., 1995;Golshani et al., 2001). Furthermore, it has been shown that NMDA receptor antagonists preferentially affect GABAergic interneurons (Grunze et al., 1996;Lewis and Moghaddam, 2006). The effect of ketamine-induced NMDA receptor hypofunction in such a selective manner would lead to the excitation rather than inhibition in excitatory neurons. ...
... It has been proposed that NMDA receptor antagonists preferentially affect inhibitory interneurons, partially because of their higher baseline activity relative to pyramidal neurons, which reduces the Mg 2+ dependent block of their NMDA receptors (Homayoun and Moghaddam, 2007). In other words, NMDA receptors on inhibitory neurons have a larger impact on neuronal activity because, as researchers have proposed, the average or baseline membrane potential of inhibitory neurons is more depolarized than that of pyramidal neurons (Lewis and Moghaddam, 2006). This property makes the inhibitory neurons more vulnerable to a removal of the voltage-dependent magnesium block. ...
Schizophrenia is an invalidating chronic disease. Warning cognitive signs and sleep disorders are seen during the psychotic transition. Brain oscillations, identifiable in an electroencephalogram, are also disturbed during the transitioning. They are involved in cognition and represent a marker of sleep quality. Oscillations are generated within the corticothalamic system and involve glutamatergic excitatory transmission. So, we tested the hypothesis that their disturbance associated with the transitioning to psychosis involves the hypofunction of glutamate receptors. Using neurophysiological approaches, we demonstrated, in sleeping rats, that ketamine, a glutamate receptor antagonist, simulates the psychosis-related disturbances. This effect was prevented by clozapine, an antipsychotic widely used in psychiatry. Mathematical tools were used to develop a neural model of psychotic transition. The present findings offer a potential therapeutic target aimed at preventing schizophrenia.
... As mentioned in the chapter Introduction, the treatment with BSO during early postnatal life did not induce behavioral changes in adult rats corresponding to positive symptoms in patients with schizophrenia [31,32], therefore it was reasonable to suppose that the occurrence of social deficits and cognitive impairment in these rats could be associated rather with more severe disturbances of glutamatergic than dopaminergic transmission [73]. The glutamatergic hypothesis of schizophrenia, as an alternative to the dopaminergic one, is based on studies in healthy humans showing that NMDA receptor antagonists, such as ketamine and phencyclidine, transiently induced features characteristic of schizophrenia, including psychosis, negative symptoms and cognitive impairments [73][74][75]. ...
... As mentioned in the chapter Introduction, the treatment with BSO during early postnatal life did not induce behavioral changes in adult rats corresponding to positive symptoms in patients with schizophrenia [31,32], therefore it was reasonable to suppose that the occurrence of social deficits and cognitive impairment in these rats could be associated rather with more severe disturbances of glutamatergic than dopaminergic transmission [73]. The glutamatergic hypothesis of schizophrenia, as an alternative to the dopaminergic one, is based on studies in healthy humans showing that NMDA receptor antagonists, such as ketamine and phencyclidine, transiently induced features characteristic of schizophrenia, including psychosis, negative symptoms and cognitive impairments [73][74][75]. For a long time, it has been thought that the neurotransmitter glutamate pool, accounting for 50-60% of the total glutamate pool, derives from glutamine-glutamate shuttle between neurons and glia, while a much smaller amount of glutamate transmitter is produced by the glycolysis and tricarboxylic acid cycle [76][77][78]. ...
Treatment of negative symptoms and cognitive disorders in patients with schizophrenia is still a serious clinical problem. The aim of our study was to compare the efficacy of chronic administration of the atypical antipsychotic drug aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy}-3,4-dihydro-2(1H)-quinolinone; ARI) and the well-known antioxidant N-acetylcysteine (NAC) both in alleviating schizophrenia-like social and cognitive deficits and in reducing the decreases in the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC) and hippocampus (HIP) of adult Sprague-Dawley rats, that have been induced by chronic administration of the model compound L-buthionine-(S, R)-sulfoximine (BSO) during the early postnatal development (p5–p16). ARI was administered at doses of 0.1 and 0.3 mg/kg while NAC at doses of 10 and 30 mg/kg, alone or in combination. Administration of higher doses of ARI or NAC alone, or co-treatment with lower, ineffective doses of these drugs significantly improved social and cognitive performance as assessed in behavioral tests. Both doses of NAC and 0.3 mg/kg of ARI increased the expression of BDNF mRNA in the PFC, while all doses of these drugs and their combinations enhanced the levels of BDNF protein in this brain structure. In the HIP, only 0,3 mg/kg ARI increased the levels of both BDNF mRNA and its protein. These data show that in the rat BSO-induced neurodevelopmental model of schizophrenia, ARI and NAC differently modulated BDNF levels in the PFC and HIP.
... Dys-functions in neurotransmission systems-including neurotransmitters, their receptors, transporters, and all intracellular processes coupled to the activation of receptors for neurotransmitters and growth factors-lead to deficits in neuronal transmission at chemical synapses with severe consequences on brain processes and cognitive functions. Mounting evidence [27,93,[195][196][197][198] indicates that an imbalance of major excitatory and inhibitory neurotransmitter systems in the brain (dopamine, serotonin, glutamate and GABA) underlies the cognitive deficits and symptoms observed in both SCZ and BIP patients. ...
... Recent evidence suggests that abnormalities in serotonin activity also play an important role in psychiatric disorders [198,211]. Postmortem studies indicate altered binding density of serotonin (5-HT) receptor subtypes 5-HT 1A and 5-HT 2A and abnormal levels of 5-hydroxyindoleacetic acid (5HIAA) and its precursor tryptophan [212][213][214]. Abnormal expression of several noradrenaline (NE)-and 5-HT-related genes have been also found in BIP patients [215]. ...
Schizophrenia (SCZ) and bipolar disorder (BIP) are severe mental disorders with a considerable disease burden worldwide due to early age of onset, chronicity, and lack of efficient treatments or prevention strategies. Whilst our current knowledge is that SCZ and BIP are highly heritable and share common pathophysiological mechanisms associated with cellular signaling, neurotransmission, energy metabolism, and neuroinflammation, the development of novel therapies has been hampered by the unavailability of appropriate models to identify novel targetable pathomechanisms. Recent data suggest that neuron–glia interactions are disturbed in SCZ and BIP, and are modulated by estrogen (E2). However, most of the knowledge we have so far on the neuromodulatory effects of E2 came from studies on animal models and human cell lines, and may not accurately reflect many processes occurring exclusively in the human brain. Thus, here we highlight the advantages of using induced pluripotent stem cell (iPSC) models to revisit studies of mechanisms underlying beneficial effects of E2 in human brain cells. A better understanding of these mechanisms opens the opportunity to identify putative targets of novel therapeutic agents for SCZ and BIP. In this review, we first summarize the literature on the molecular mechanisms involved in SCZ and BIP pathology and the beneficial effects of E2 on neuron–glia interactions. Then, we briefly present the most recent developments in the iPSC field, emphasizing the potential of using patient-derived iPSCs as more relevant models to study the effects of E2 on neuron–glia interactions.
... Circuits for cortical feedforward inhibition are now relatively well defined, and may principally involve fast-spiking, parvalbumin-expressing (PV+) inhibitory interneurons (Agmon and Connors, 1992;Gibson et al., 1999;Dantzker and Callaway, 2000;Gonchar and Burkhalter, 2003). It is also now well established that PV+ interneurons are compromised in schizophrenia (reviewed by (Benes and Berretta, 2001;Lewis et al., 2005;Lewis and Moghaddam, 2006;Lewis, 2014;Gonzalez-Burgos et al., 2015)). ...
... (Piantadosi and Floresco, 2014)). It also matches decades of work linking relevance impairments in schizophrenia (Mcghie and Chapman, 1961;Venables, 1964;Lang and Buss, 1965;McGhie, 1970;Garmezy, 1977;Johnson, 1985;Kapur, 2003) with evidence that inhibitory neurons, and in particular classes of inhibitory neurons supporting feed-forward inhibition, may be differentially compromised in the disease (Benes and Berretta, 2001;Lewis et al., 2005;Lewis and Moghaddam, 2006;Lewis, 2014;Gonzalez-Burgos et al., 2015;Krystal et al., 2017). Finally, the third mechanism, wherein inhibitory interneuron plasticity is the means for learning to differentiate relevant versus irrelevant stimuli, is consistent with findings that the neural connections supporting feed-forward inhibition are plastic (Kullmann et al., 2012;Kullmann and Lamsa, 2011;Bartos et al., 2011), in some cases requiring NMDA receptors with a well established importance for associative plasticity (Lamsa et al., 2007(Lamsa et al., , 2005Le Roux et al., 2013). ...
Symptoms of schizophrenia may arise from a failure of cortical circuits to filter-out irrelevant inputs. Schizophrenia has also been linked to disruptions to cortical inhibitory interneurons, consistent with the possibility that in the normally functioning brain, these cells are in some part responsible for determining which inputs are relevant and which irrelevant. Here, we develop an abstract but biologically plausible neural network model that demonstrates how the cortex may learn to ignore irrelevant inputs through plasticity processes affecting inhibition. The model is based on the proposal that the amount of excitatory output from a cortical circuit encodes expected magnitude of reward or punishment (”relevance”), which can be trained using a temporal difference learning mechanism acting on feed-forward inputs to inhibitory interneurons. The model exhibits learned irrelevance and blocking, which become impaired following disruptions to inhibitory units. When excitatory units are connected to a competitive-learning output layer, the relevance code is capable of modulating learning and activity. Accordingly, the combined network is capable of recapitulating published experimental data linking inhibition in frontal cortex with fear learning and expression. Finally, the model demonstrates how relevance learning can take place in parallel with other types of learning, through plasticity rules involving inhibitory and excitatory components respectively. Altogether, this work offers a theory of how the cortex learns to selectively inhibit inputs, providing insight into how relevance-assignment problems may emerge in schizophrenia.
... Converging preclinical and clinical evidence support the critical involvement of NMDAR hypofunction in cognitive deficits [30,[70][71][72][73]. To our knowledge, this is the first time an NMDAR hypofunction mechanism-based biomarker has been associated with cognitive scores in FEP patients stratified by treatment resistance. ...
This study aims to determine whether 1) individuals with treatment-resistant schizophrenia display early cognitive impairment compared to treatment-responders and healthy controls and 2) N-methyl-D-aspartate-receptor hypofunction is an underlying mechanism of cognitive deficits in treatment-resistance. In this case‒control 3-year-follow-up longitudinal study, n = 697 patients with first-episode psychosis, aged 18 to 35, were screened for Treatment Response and Resistance in Psychosis criteria through an algorithm that assigns patients to responder, limited-response or treatment-resistant category (respectively resistant to 0, 1 or 2 antipsychotics). Assessments at baseline: MATRICS Consensus Cognitive Battery; N-methyl-D-aspartate-receptor co-agonists biomarkers in brain by MRS (prefrontal glutamate levels) and plasma (D-serine and glutamate pathways key markers). Patients were compared to age- and sex-matched healthy controls (n = 114). Results: patient mean age 23, 27% female. Treatment-resistant (n = 51) showed lower scores than responders (n = 183) in processing speed, attention/vigilance, working memory, verbal learning and visual learning. Limited responders (n = 59) displayed an intermediary phenotype. Treatment-resistant and limited responders were merged in one group for the subsequent D-serine and glutamate pathway analyses. This group showed D-serine pathway dysregulation, with lower levels of the enzymes serine racemase and serine-hydroxymethyltransferase 1, and higher levels of the glutamate-cysteine transporter 3 than in responders. Better cognition was associated with higher D-serine and lower glutamate-cysteine transporter 3 levels only in responders; this association was disrupted in the treatment resistant group. Treatment resistant patients and limited responders displayed early cognitive and persistent functioning impairment. The dysregulation of NMDAR co-agonist pathways provides underlying molecular mechanisms for cognitive deficits in treatment-resistant first-episode psychosis. If replicated, our findings would open ways to mechanistic biomarkers guiding response-based patient stratification and targeting cognitive improvement in clinical trials.
... Crucially, it has been hypothesized that GABAergic deficit-induced changes in neural excitability and reduced conversion of glutamate to GABA may be responsible for the increased glutamate concentrations found in the brain of psychiatric patients [349]. However, given the evidence for reduced rather than increased brain content of glutamate in psychiatric patients [350], the relationship between GABAergic and glutamatergic transmission changes needs to be further elucidated. ...
Investigating the biophysiological substrates of psychiatric illnesses is of great interest to our understanding of disorders' etiology, the identification of reliable biomarkers, and potential new therapeutic avenues. Schizophrenia represents a consolidated model of γ alterations arising from the aberrant activity of parvalbumin-positive GABAergic interneurons, whose dysfunction is associated with perineuronal net impairment and neuroinflammation. This model of pathogenesis is supported by molecular, cellular, and functional evidence. Proof for alterations of γ oscillations and their underlying mechanisms has also been reported in bipolar disorder and represents an emerging topic for major depressive disorder. Although evidence from animal models needs to be further elucidated in humans, the pathophysiology of γ-band alteration represents a common denominator for different neuropsychiatric disorders. The purpose of this narrative review is to outline a framework of converging results in psychiatric conditions characterized by γ abnormality, from neurochemical dysfunction to alterations in brain rhythms.
... A long-standing hypothesis is that defects in the GABAergic inhibitory system can contribute to SCZ (86). Additionally, cognitive dysfunction in SCZ could be the result of dysfunction in the convergence of glutamatergic and GABAergic systems (87). One possible outcome of decreased feed-forward excitation on PV cells in the male PV-mC4-KI mouse is a disruption in the dynamics of excitation and inhibition, tipping the scales towards the side of unchecked excitation and excess glutamatergic release. ...
Fast-spiking parvalbumin (PV)-positive cells are key players in orchestrating pyramidal neuron activity and thus serve an indispensable role in cognitive function and emotional regulation. Feed-forward excitatory inputs, essential for the function of PV cells, are disrupted in various neurological conditions, including schizophrenia (SCZ). However, it is not clear how disease-associated stressors such as immune dysregulation contribute to defects in particular cell types or neuronal circuits. We have developed a novel transgenic mouse line that permits conditional, cell-type specific overexpression (OE) of the immune complement component 4 (C4) gene, which is highly associated with SCZ. Using this genetic approach, we demonstrate that specific global OE of mouse C4 (mC4) in PV cells causes pathological anxiety-like behavior in male, but not female mice. In the male medial prefrontal cortex (mPFC), this sexually dimorphic behavioral alteration was accompanied by a reduction in excitatory inputs to fast-spiking cells and an enhancement of their inhibitory connections. Additionally, in PV cells, elevated levels of mC4 led to contrasting effects on the excitability of cortical cells. In males, PV cells and pyramidal neurons exhibited reduced excitability, whereas in females, PV cells displayed heightened excitability. Contrary to the behavioral changes seen with elevated mC4 levels in PV cells, pan-neuronal overexpression did not increase anxiety-like behaviors. This indicates that mC4 dysfunction, particularly in fast-spiking cells, has a more significant negative impact on anxiety-like behavior than widespread alterations in the neuronal complement. Consequently, by employing a novel mouse model, we have demonstrated a causal relationship between the conditional overexpression of the schizophrenia risk gene C4 in fast-spiking neurons and the susceptibility of cortical circuits in male mice, resulting in changes in behaviors associated with prefrontal cortex function.
... Given that many cognitive symptoms of SZ are thought to be linked to a mismatch between inhibitory GABA and excitatory glutamate neurotransmission in the dorsolateral prefrontal cortex. SZ cognitive deficits may be partly caused by MCHTAP expression or function dysregulation that disrupts GABAergic/glutamatergic balance [83][84][85]. ECM proteins are involved in neuronal cell migration, axonal growth, myelination, and the formation and maintenance of the neuromuscular junction at the BBB [86]. The ECM-integrin signaling pathway may regulate cell adhesion and signaling, endosomal trafficking, CSK dynamics, and gene expression at all stages of nervous system development, maintenance, degeneration, and regeneration [87,88]. ...
Schizophrenia (SZ) is a chronic and devastating mental illness that affects around 20 million individuals worldwide. Cognitive deficits and structural and functional changes of the brain, abnormalities of brain ECM components, chronic neuroinflammation, and devastating clinical manifestation during SZ are likely etiological factors shown by affected individuals. However, the pathophysiological events associated with multiple regulatory pathways involved in the brain of this complex disorder are still unclear. This study aimed to develop a pipeline based on bioinformatics and systems biology approaches for identifying potential therapeutic targets involving possible biological mechanisms from SZ patients and healthy volunteers. About 420 overlapping differentially expressed genes (DEGs) from three RNA-seq datasets were identified. Gene ontology (GO), and pathways analysis showed several biological mechanisms enriched by the commonly shared DEGs, including extracellular matrix organization (ECM) organization, collagen fibril organization, integrin signaling pathway, inflammation mediated by chemokines and cytokines signaling pathway, and GABA-B receptor II and IL4 mediated signaling. Besides, 15 hub genes (FN1, COL1A1, COL3A1, COL1A2, COL5A1, COL2A1, COL6A2, COL6A3, MMP2, THBS1, DCN, LUM, HLA-A, HLA-C, and FBN1) were discovered by comprehensive analysis, which was mainly involved in the ECM organization and inflammatory signaling pathway. Furthermore, the miRNA target of the hub genes was analyzed with the random-forest-based approach software miRTarBase. In addition, the transcriptional factors and protein kinases regulating overlapping DEGs in SZ, namely, SUZ12, EZH2, TRIM28, TP53, EGR1, CSNK2A1, GSK3B, CDK1, and MAPK14, were also identified. The results point to a new understanding that the hub genes (fibronectin 1, collagen, matrix metalloproteinase-2, and lumican) in the ECM organization and inflammatory signaling pathways may be involved in the SZ occurrence and pathogenesis.
... Therefore, NMDAR subtype switching renders NMDARs vulnerable to genetic and environmental risk factors (Spear, 2000). A glutamatergic model mediated by NMDARs can provide an alternative way of conceptualizing schizophrenia-associated brain abnormalities (Harrison and Weinberger, 2005;Lewis and Moghaddam, 2006;Lisman et al., 2008). N-methyl-D-aspartate receptor hypofunction is a convergence point for the progression and symptoms of SZ, especially cognitive deficits (Moghaddam, 2003;Coyle, 2006;Lisman et al., 2008;Marek, 2010;Cohen et al., 2015;Nakazawa et al., 2017). ...
N-methyl-D-aspartate receptors (NMDA) are glutamate-gated ion channels critical for synaptic transmission and plasticity. A slight variation of NMDAR expression and function can result in devastating consequences, and both hyperactivation and hypoactivation of NMDARs are detrimental to neural function. Compared to NMDAR hyperfunction, NMDAR hypofunction is widely implicated in many neurological disorders, such as intellectual disability, autism, schizophrenia, and age-related cognitive decline. Additionally, NMDAR hypofunction is associated with the progression and manifestation of these diseases. Here, we review the underlying mechanisms of NMDAR hypofunction in the progression of these neurological disorders and highlight that targeting NMDAR hypofunction is a promising therapeutic intervention in some neurological disorders.
... In this work, we observed that PHB2 protein levels changed in relation with the FAB scores in the DLPFC of SZ patients, which highlight that people with SZ with higher levels of PHB2 may have poorer cognitive performances. Dysfunctions in glutamatergic neurotransmission systems and mitochondrial dysfunctions have been implicated in the emergence of these symptoms in SZ [53][54][55]; however, to the best of our knowledge, no studies are available for PHB2 protein in this context and more studies are needed to elucidate by which mechanisms PHB2 could contribute to the cognitive impairments observed in SZ. Recently, several POP inhibitors have been developed for the treatment of CNS disorders and it has been suggested that the POP inhibitor, IPR19, improves cognitive performance and it might have therapeutic potential for the treatment of the cognitive deficits associated with SZ [21,22]. ...
Cognitive impairment represents one of the core features of schizophrenia. Prolyl Oligopeptidase (POP) inhibition is an emerging strategy for compensating cognitive deficits in hypoglutamatergic states such as schizophrenia, although little is known about how POP inhibitors exert their pharmacological activity. The mitochondrial and nuclear protein Prohibitin 2 (PHB2) could be dysregulated in schizophrenia. However, altered PHB2 levels in schizophrenia linked to N-methyl-D-aspartate receptor (NMDAR) activity and cognitive deficits are still unknown. To shed light on this, we measured the PHB2 levels by immunoblot in a postmortem dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects, in the frontal pole of mice treated with the NMDAR antagonists phencyclidine and dizocilpine, and in rat cortical astrocytes and neurons treated with dizocilpine. Mice and cells were treated in combination with the POP inhibitor IPR19. The PHB2 levels were also analyzed by immunocytochemistry in rat neurons. The PHB2 levels increased in DLPFC in cases of chronic schizophrenia and were associated with cognitive impairments. NMDAR antagonists increased PHB2 levels in the frontal pole of mice and in rat astrocytes and neurons. High levels of PHB2 were found in the nucleus and cytoplasm of neurons upon NMDAR inhibition. IPR19 restored PHB2 levels in the acute NMDAR inhibition. These results show that IPR19 restores the upregulation of PHB2 in an acute NMDAR hypoactivity stage suggesting that the modulation of PHB2 could compensate NMDAR-dependent cognitive impairments in schizophrenia.
... In recent decades, this has led to the glutamate (GLU) hypothesis, which also plays a key role in schizophrenia pathophysiology, particularly in the development of negative symptoms and cognitive dysfunction [2,3]. 2 of 19 Evidence from pharmacological, postmortem, brain imaging and genetic studies supports the role of glutamatergic dysregulation in schizophrenia [4]. This theory was proposed based on the capacity of N-methyl-D-aspartate (NMDA) GLU receptor antagonists, such as ketamine, to mimic the positive, negative and cognitive symptoms of schizophrenia in healthy individuals and to exacerbate psychotic symptoms and cognitive decline in patients with the disease [5]. The blockade of NMDA receptors in gamma-aminobutyric (GABAergic) interneurons, which express calcium-binding protein parvalbumin, generates a hyperglutamatergic condition as a consequence of decreased inhibitory control of excitatory pyramidal neurons. ...
Current antipsychotics (APs) effectively control positive psychotic symptoms, mainly by blocking dopamine (DA) D2 receptors, but have little effect on negative and cognitive symptoms. Increased glutamate (GLU) release would trigger neurotoxicity, leading to apoptosis and synaptic pruning, which is involved in the pathophysiology of schizophrenia. New pharmacological strategies are being developed such as positive allosteric modulators (PAMs) of the metabotropic GLU receptor 2 (mGluR2) that inhibit the presynaptic release of GLU. We previously reported that treatment of adult mice with JNJ-46356479 (JNJ), a recently developed mGluR2 PAM, partially improved neuropathological deficits and schizophrenia-like behavior in a postnatal ketamine mouse model. In the present study, we evaluated, for the first time, the putative neuroprotective and antiapoptotic activity of JNJ in a human neuroblastoma cell line and compared it with the effect of clozapine (CLZ) as a clinical AP with the highest efficacy and with apparent utility in managing negative symptoms. Specifically, we measured changes in cell viability, caspase 3 activity and apoptosis, as well as in the expression of key genes involved in survival and cell death, produced by CLZ and JNJ alone and in combination with a high DA or GLU concentration as apoptosis inducers. Our results suggest that JNJ is not neurotoxic and attenuates apoptosis, particularly by decreasing the caspase 3 activation induced by DA and GLU, as well as increasing and decreasing the number of viable and apoptotic cells, respectively, only when cultures were exposed to GLU. Its effects seem to be less neurotoxic and more neuroprotective than those observed with CLZ. Moreover, JNJ partially normalized altered expression levels of glycolytic genes, which could act as a protective factor and be related to its putative neuroprotective effect. More studies are needed to define the mechanisms of action of this GLU modulator and its potential to become a novel therapeutic agent for schizophrenia.
... Glutamatergic dysregulation is one of the main pathophysiological theories of SZ. This theory arose from observations that N-methyl-D-aspartate (NMDA) glutamate receptor antagonists, such as ketamine (KET), phencyclidine (PCP), or dizocilpine (MK-801), not only mimic the positive, negative, and cognitive symptoms of SZ in healthy individuals but also exacerbate the psychotic symptoms and cognitive decline in patients with the disease [6,7]. The blockade of NMDA receptors in gamma-aminobutyric (GABA)ergic interneurons, which express parvalbumin (PV), may generate a hyperglutamatergic condition because of the decreased inhibitory control of excitatory pyramidal neurons, leading to neurotoxicity, apoptosis, and synaptic pruning in critical brain areas [8,9]. ...
Positive allosteric modulators of the metabotropic glutamate receptor 2 (mGluR2), such as JNJ-46356479 (JNJ), may mitigate the glutamate storm during the early stages of schizophrenia (SZ), which could be especially useful in the treatment of cognitive and negative symptoms. We evaluated the efficacy of early treatment with JNJ or clozapine (CLZ) in reversing behavioral and neuropathological deficits induced in a postnatal ketamine (KET) mouse model of SZ. Mice exposed to KET (30 mg/kg) on postnatal days (PND) 7, 9, and 11 received JNJ or CLZ (10 mg/kg) daily in the adolescent period (PND 35–60). Mice exposed to KET did not show the expected preference for a novel object or for social novelty, but they recovered this preference with JNJ treatment. Similarly, KET group did not show the expected dishabituation in the fifth trial, but mice treated with JNJ or CLZ recovered an interest in the novel animal. Neuronal immunoreactivity also differed between treatment groups with mice exposed to KET showing a reduction in parvalbumin positive cells in the prefrontal cortex and decreased c-Fos expression in the hippocampus, which was normalized with the pharmacological treatment. JNJ-46356479 treatment in early stages may help improve the cognitive and negative symptoms, as well as certain neuropathological deficits, and may even obtain a better response than CLZ treatment. This may have relevant clinical translational applications since early treatment with mGluR2 modulators that inhibit glutamate release at the onset of critical phases of SZ may prevent or slow down the clinical deterioration of the disease.
... The interaction between the glutamate and dopamine systems in schizophrenia is that hypofunction of the glutamate NMDA receptor on GABA interneurons leads to disinhibition of glutamatergic projections on the dopamine system in the midbrain, increased glutamate release and ultimately increased activation of dopaminergic neurons (Howes et al., 2015). The convergence of GABA impairment and glutamate neurotransmission in the dorsolateral prefrontal cortex could explain the impairment of certain cognitive functions in schizophrenia (Lewis and Moghaddam, 2006). ...
Both the discovery of biomarkers of schizophrenia and the verification of biological hypotheses of schizophrenia are an essential part of the process of understanding the etiology of this mental disorder. Schizophrenia has long been considered a neurodevelopmental disease whose symptoms are caused by impaired synaptic signal transduction and brain neuroplasticity. Both the onset and chronic course of schizophrenia are associated with risk factors-induced disruption of brain function and the establishment of a new homeostatic setpoint characterized by biomarkers. Different risk factors and biomarkers can converge to the same symptoms of schizophrenia, suggesting that the primary cause of the disease can be highly individual. Schizophrenia-related biomarkers include measurable biochemical changes induced by stress (elevated allostatic load), mitochondrial dysfunction, neuroinflammation, oxidative and nitrosative stress, and circadian rhythm disturbances. Here is a summary of selected valid biological hypotheses of schizophrenia formulated based on risk factors and biomarkers, neurodevelopment, neuroplasticity, brain chemistry, and antipsychotic medication. The integrative neurodevelopmental-vulnerability-neurochemical model is based on current knowledge of the neurobiology of the onset and progression of the disease and the effects of antipsychotics and psychotomimetics and reflects the complex and multifactorial nature of schizophrenia.
... In mature neurons, synaptic plasticity is responsible for synapse remodeling during experience. Genetic mutations or pathology leading to altered excitatory or inhibitory neurotransmission or impaired synaptogenesis typically result in deficits in synaptic plasticity, a common feature in neurodevelopmental and neurological disorders (Rudolph and Möhler, 2014;Mele et al., 2019), including autism (Hansel, 2019;Sohal and Rubenstein, 2019), down syndrome (Galdzicki et al., 2001;Schulz et al., 2019), schizophrenia (Lewis and Moghaddam, 2006;Gao and Penzes, 2015), epilepsy (Needs et al., 2019), and neurodegenerative disorders (Smith-Dijak et al., 2019;Bi et al., 2020). Uncovering the mechanisms regulating synaptic plasticity will help illuminate how disruptions in GABAergic and glutamatergic function influence the pathophysiology of these disorders, identify new therapeutic targets, and reveal potential impacts of pharmacologically targeting these receptors. ...
Synaptic plasticity is a critical process that regulates neuronal activity by allowing neurons to adjust their synaptic strength in response to changes in activity. Despite the high proximity of excitatory glutamatergic and inhibitory GABAergic postsynaptic zones and their functional integration within dendritic regions, concurrent plasticity has historically been underassessed. Growing evidence for pathological disruptions in the excitation and inhibition (E/I) balance in neurological and neurodevelopmental disorders indicates the need for an improved, more “holistic” understanding of synaptic interplay. There continues to be a long-standing focus on the persistent strengthening of excitation (excitatory long-term potentiation; eLTP) and its role in learning and memory, although the importance of inhibitory long-term potentiation (iLTP) and depression (iLTD) has become increasingly apparent. Emerging evidence further points to a dynamic dialogue between excitatory and inhibitory synapses, but much remains to be understood regarding the mechanisms and extent of this exchange. In this mini-review, we explore the role calcium signaling and synaptic crosstalk play in regulating postsynaptic plasticity and neuronal excitability. We examine current knowledge on GABAergic and glutamatergic synapse responses to perturbances in activity, with a focus on postsynaptic plasticity induced by short-term pharmacological treatments which act to either enhance or reduce neuronal excitability via ionotropic receptor regulation in neuronal culture. To delve deeper into potential mechanisms of synaptic crosstalk, we discuss the influence of synaptic activity on key regulatory proteins, including kinases, phosphatases, and synaptic structural/scaffolding proteins. Finally, we briefly suggest avenues for future research to better understand the crosstalk between glutamatergic and GABAergic synapses.
... Attenuated psychosis syndrome (APS) and schizophrenia have been associated with abnormalities in glutamatergic neurotransmission related to impaired N-methyl-D-aspartic acid (NMDA) receptor signalling [1][2][3]. Activation of the NMDA receptor leads to postsynaptic signalling events via increases in second messengers such as cyclic guanosine monophosphate (cGMP) [4]. It has been suggested that during NMDA receptor hypofunction, inhibition of phosphodiesterase 9A (PDE9A), which hydrolyses cGMP, could increase intracellular cGMP concentrations, thus restoring NMDA receptor signalling. ...
Purpose
The potent, selective phosphodiesterase-9A inhibitor BI 409306 may be beneficial for patients with attenuated psychosis syndrome and could prevent relapse in patients with schizophrenia. Transient BI 409306-dependent increases in heart rate (HR) demonstrated previously necessitated cardiac safety characterisation. We evaluated cardiac effects of BI 409306 in healthy volunteers during rest and exercise.
Methods
In this double-blind, three-way crossover study, volunteers received placebo, BI 409306 50 mg or 200 mg in randomised order (same treatment on Days 1 [resting] and 3 [exercise]). Cardiopulmonary exercise testing was performed twice post treatment on Day 3 of each period. BI 409306-mediated effects on placebo-corrected change from baseline in resting HR (ΔΔHR) were evaluated based on exposure–response analysis and a random coefficient model. Adverse events (AEs) were recorded.
Results
Overall, 19/20 volunteers completed. Resting ΔΔHR versus BI 409306 concentration yielded a slope of 0.0029 beats/min/nmol/L. At the geometric mean (gMean) maximum plasma concentration ( C max ) for BI 409306 50 and 200 mg, predicted mean (90% CI) ΔΔHRs were 0.80 (− 0.76, 2.36) and 5.46 (2.44, 8.49) beats/min, respectively. Maximum adjusted mean differences from placebo (90% CI) in resting HR for BI 409306 50 and 200 mg were 3.85 (0.73, 6.97) and 4.93 (1.69, 8.16) beats/min. Maximum differences from placebo in resting HR occurred at/near gMean C max and returned to baseline after approximately 4 h. The proportion of volunteers with AEs increased with BI 409306 dose.
Conclusion
Observed hemodynamic effects following BI 409306 administration were of low amplitude, transient, and followed the pharmacokinetic profile of BI 409306.
... Cette hypofonction des récepteurs NMDA pourrait être à l'origine d'une augmentation secondaire du glutamate qui a pu être étudiée en microdialyse chez le rat (Moghaddam et al., 1997), et qui entraîne secondairement une diminution de l'activité des interneurones GABAergiques par neurotoxicité (Olney & Farber, 1995). Cette diminution est elle-même à l'origine d'une désinhibition des neurones pyramidaux glutamatergiques (Lewis & Moghaddam, 2006) qui pourrait médier l'hyperdopaminergie mésolimbique retrouvée dans la schizophrénie (Marsman et al., 2014). Il existe, en effet, des arguments pour lier l'activité glutamatergique et l'activité dopaminergique. ...
Les êtres humains doivent être capables d’intégrer de nombreux stimuli perceptifs mais également de filtrer en priorité les seules informations dignes d’intérêt. Ces stimuli sont priorisés en fonction de leur saillance. Le réseau cérébral de la saillance est composé de l’insula antérieure, du cortex cingulaire antérieur dorsal, de l’amygdale, du striatum ventral, et de la substance noire/aire tegmentale ventrale. Ce réseau focalise l’attention et facilite l’accès à la mémoire de travail une fois qu’un évènement saillant est détecté. Le réseau de saillance joue ainsi un rôle crucial dans la balance cognitive entre stimuli externes et processus mentaux internes. De nombreuses études ont démontré l’existence de liens entre ce réseau et le stress. De même, le réseau de saillance a été impliqué dans de nombreuses pathologies psychiatriques ou neurologiques, dont la démence fronto-temporale, les troubles de l’humeur et anxieux, la schizophrénie, les addictions ou encore la douleur. Plus spécifiquement, une implication du réseau de saillance dans les expériences intrusives a été suggérée, notamment au cours des hallucinations dans la schizophrénie, et potentiellement lors des reviviscences post-traumatiques dans le trouble de stress post-traumatique. L’objectif de ce travail de thèse était d’étudier plus précisément le rôle du réseau de saillance dans les phénomènes intrusifs dans ces deux pathologies. Une première partie est consacrée à l’étude des hallucinations dans la schizophrénie, et une seconde porte sur l’étude des reviviscences post-traumatiques dans le trouble de stress post-traumatique. Nous avons tout d’abord étudié les bases neurales de la saillance dans la schizophrénie, en réalisant une méta-analyse basée sur les coordonnées fonctionnelles (en imagerie par résonance magnétique) d’études se focalisant sur les processus de récompense. Nous avons ainsi montré que l’hypoactivation du striatum ventral retrouvée chez les patients souffrant de schizophrénie lors de ces tâches était corrélée aux symptômes positifs du trouble. Plusieurs études ‘trait’ et ‘état’ ont proposé que le réseau de saillance puisse jouer un rôle modulateur dans les expériences hallucinatoires. Dans une deuxième étude, nous avons donc validé une méthode de capture hallucinatoire à même de comparer le décours temporel des aires hyperactivées dans ces expériences, avec celui des différents réseaux fonctionnels de repos, étape indispensable pour la mesure dynamique du réseau de saillance dans ces phénomènes. Enfin, dans une troisième étude, nous avons étudié le rôle joué par le réseau de saillance, et en particulier de l’insula antérieure, dans la réponse au traitement dans le trouble de stress post-traumatique. En effet, les bases neurales de la réponse au traitement sont encore peu connues, notamment via des mesures de connectivité effective. Nous avons ainsi pu montrer l’importance du rôle modulateur de l’insula antérieure dans la diminution des reviviscences post-traumatiques. Ces résultats laissent entrevoir plusieurs applications concrètes en psychiatrie. En particulier, l’amélioration des connaissances physiopathologiques des phénomènes intrusifs, à la fois dans la schizophrénie et le trouble de stress post-traumatique, avec la perspective de développer des méthodes de capture des reviviscences post-traumatiques sur le modèle de la capture hallucinatoire, ouvre des possibilités d’avancées dans le champ de la médecine personnalisée dans ces deux pathologies.
... Existing attempts to use brain stimulation as a therapeutic intervention in SZ have largely focused on stimulating dorsolateral prefrontal cortex with mixed outcomes (38,39). The evidence for prefrontal cortex (PFC) stimulation sites in SZ is supported by its abnormal activation during cognitive control (4,40), its disrupted connectivity profile (41,42), and neurotransmitter regulation (43). Our data-driven simulation complements these observations by corroborating the role of PFC in SZ dysfunction and providing new hypotheses to test regarding particular parietal and temporal lobe regions (see Fig. 7). ...
Cognitive dysfunction is a core feature of many brain disorders, including schizophrenia (SZ), and has been linked to aberrant brain activations. However, it is unclear how these activation abnormalities emerge. We propose that aberrant flow of brain activity across functional connectivity (FC) pathways leads to altered activations that produce cognitive dysfunction in SZ. We tested this hypothesis using activity flow mapping, an approach that models the movement of task-related activity between brain regions as a function of FC. Using functional magnetic resonance imaging data from SZ individuals and healthy controls during a working memory task, we found that activity flow models accurately predict aberrant cognitive activations across multiple brain networks. Within the same framework, we simulated a connectivity-based clinical intervention, predicting specific treatments that normalized brain activations and behavior in patients. Our results suggest that dysfunctional task-evoked activity flow is a large-scale network mechanism contributing to cognitive dysfunction in SZ.
... The decreased stimulation of hypoactive NMDA receptors on GABAergic interneurons causes an insufficient release of GABA. Since the inhibitory effect of GABA neurons on glutamate neurons is attenuated, the disinhibited glutamate neurons release abnormally high glutamate, thereby causing excitotoxic stress (Konradi and Heckers, 2003;Lewis and Moghaddam, 2006;Olney et al., 1999). Previous study reported a low NMDA receptor expression in the thalamic areas (Ibrahim et al., 2000), and a broad elevation of glutamate metabolites in the thalamus and basal ganglia of schizophrenia patients (Merritt et al., 2016;Yang et al., 2019). ...
Purpose:
Decreased serum ferritin level was recently found in schizophrenia. Whether the brain iron concentration in schizophrenia exists abnormality is of research significance. Quantitative susceptibility mapping (QSM) was used in this study to assess brain iron changes in the grey matter nuclei of patients with first-episode schizophrenia.
Methods:
The local ethics committee approved the study, and all subjects gave written informed consent. Thirty patients with first-episode schizophrenia and 30 age and gender-matched healthy controls were included in this study. QSM and effective transverse relaxation rate (R2*) maps were reconstructed from a three-dimensional multi-echo gradient-echo sequence. The inter-group differences of regional QSM values, R2* values and volumes were calculated in the grey matter nuclei, including bilateral caudate nucleus, putamen, globus pallidus, substantia nigra, red nucleus, and thalamus. The diagnostic performance of QSM and R2* was evaluated using receiver operating characteristic curve. The correlations between regional iron variations and clinical PANSS (Positive and Negative Syndrome Scale) scores were assessed using partial correlation analysis.
Results:
Compared to healthy controls, patients with first-episode schizophrenia had significantly decreased QSM values (less paramagnetic) in the bilateral substantia nigra, left red nucleus and left thalamus (p < 0.05, FDR correction). QSM proved more sensitive than R2* regarding inter-group differences. The highest diagnostic performance for first-episode schizophrenia was observed in QSM value of the left substantia nigra (area under the curve, AUC = 0.718, p = 0.004). Regional volumes of bilateral putamen and bilateral substantia nigra were increased (p < 0.05, FDR correction) in first-episode schizophrenia. However, both QSM and R2* values did not show significant correlations with PANSS scores (p > 0.05).
Conclusion:
This study reveals decreased iron concentration in grey matter nuclei of patients with first-episode schizophrenia. QSM provides superior sensitivity over R2* in the evaluation of schizophrenia-related brain iron changes. It demonstrated that QSM may be a potential biomarker for further understanding the pathophysiological mechanism of first-episode schizophrenia.
... In our study, it is difficult to explain the appearance of social and cognitive deficits in adolescence and early adulthood in the group of rats receiving BSO alone during the early postnatal life, referring only to the above-mentioned dopamine hypothesis of schizophrenia. These data show that their occurrence in the BSO-treated group may be related to disturbances in other neurotransmitter systems rather than the dopamine system [78]. Since the inhibition of GSH synthesis may impact the function of NMDA receptors [14,62,69], it seems that impairment of the excitation-inhibition balance during the early postnatal life plays a decisive role in the occurrence of social and cognitive deficits in the BSO-treated rats later in life. ...
Growing body of evidence points to dysregulation of redox status in the brain as an important factor in the pathogenesis of schizophrenia. The aim of our study was to evaluate the effects of l-buthionine-(S,R)-sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, and 1-[2-Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909), a dopamine reuptake inhibitor, given alone or in combination, to Sprague–Dawley pups during early postnatal development (p5–p16), on the time course of the onset of schizophrenia-like behaviors, and on the expression of brain-derived neurotrophic factor (BDNF) mRNA and its protein in the prefrontal cortex (PFC) and hippocampus (HIP) during adulthood. BSO administered alone decreased the levels of BDNF mRNA and its protein both in the PFC and HIP. Treatment with the combination of BSO + GBR 12909 also decreased BDNF mRNA and its protein in the PFC, but in the HIP, only the level of BDNF protein was decreased. Schizophrenia-like behaviors in rats were assessed at three time points of adolescence (p30, p42–p44, p60–p62) and in early adulthood (p90–p92) using the social interaction test, novel object recognition test, and open field test. Social and cognitive deficits first appeared in the middle adolescence stage and continued to occur into adulthood, both in rats treated with BSO alone or with the BSO + GBR 12909 combination. Behavior corresponding to positive symptoms in humans occurred in the middle adolescence period, only in rats treated with BSO + GBR 12909. Only in the latter group, amphetamine exacerbated the existing positive symptoms in adulthood. Our data show that rats receiving the BSO + GBR 12909 combination in the early postnatal life reproduced virtually all symptoms observed in patients with schizophrenia and, therefore, can be considered a valuable neurodevelopmental model of this disease.
... It is mostly likely that the elevated GABA level in the mPFC could be the overcompensation of a subclass of GABAergic neurons rather than PV interneurons (Kegeles et al., 2012). The deficits in GABAergic (fast-spiking interneurons) transmission upon pyramidal neurons lead to glutamate elevation (Lewis and Moghaddam, 2006;Lisman et al., 2008), which in turn stimulates the rest of the subclasses of GABAergic interneurons to compensate the reduced GABA synthesis of PV neurons (Kegeles et al., 2012). Moreover, spatial distributions of interneuron subtypes could underlie regional signaling differences across the cortical sheet, as BOLD functional magnetic resonance imaging (Anderson et al., 2020) has suggested a heterogeneous distribution and region-specific function of interneurons. ...
Despite strenuous studies since the last century, the precise cause and pathology of schizophrenia are still largely unclear and arguably controversial. Although many hypotheses have been proposed to explain the etiology of schizophrenia, the definitive genes or core pathological mechanism remains absent. Among these hypotheses, however, GABAergic dysfunction stands out as a common feature consistently reported in schizophrenia, albeit a satisfactory mechanism that could be exploited for therapeutic purpose has not been developed yet. This review is focusing on the progress made to date in the field in terms of understanding the mechanisms involving dysfunctional GABAergic system and loops identified in schizophrenia research.
... cognitive symptoms of schizophrenia in healthy volunteers and exacerbates psychotic symptoms and cognitive decline in individuals with the disease 65,66 . A recent meta-analysis of post-mortem studies found that PV+ interneurons were reduced in the PFC of patients with schizophrenia 67 . ...
Schizophrenia disorder remains an unsolved puzzle. However, the integration of recent findings from genetics, molecular biology, neuroimaging, animal models and translational clinical research offers evidence that the synaptic overpruning hypothesis of schizophrenia needs to be reassessed. During a critical period of neurodevelopment and owing to an imbalance of excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons, a regionally-located glutamate storm might occur, triggering excessive dendritic pruning with the activation of local dendritic apoptosis machinery. The apoptotic loss of dendritic spines would be aggravated by microglia activation through a recently described signaling system from complement abnormalities and proteins of the MHC, thus implicating the immune system in schizophrenia. Overpruning of dendritic spines coupled with aberrant synaptic plasticity, an essential function for learning and memory, would lead to brain misconnections and synaptic inefficiency underlying the primary negative symptoms and cognitive deficits of schizophrenia. This driving hypothesis has relevant therapeutic implications, including the importance of pharmacological interventions during the prodromal phase or the transition to psychosis, targeting apoptosis, microglia cells or the glutamate storm. Future research on apoptosis and brain integrity should combine brain imaging, CSF biomarkers, animal models and cell biology.
... Lines of evidence have shown that dysbindin-deficient mice show decreased glutamate release [46,47] and GABAergic transmission [48,49] in the prefrontal cortex, which all are interlinked with presynaptic calcium transients. In addition, this impaired neurotransmission has been implicated in the etiology of schizophrenia [29,50,51]. Further work is required to identify whether the dysbindin-mediated regulation of calcium homeostasis is on the same line with previously known presynaptic functions of dysbindin mediating the trafficking and priming of synaptic vesicles. ...
Mitochondrial movement in neurons is finely regulated to meet the local demand for energy and calcium buffering. Elaborate transport machinery including motor complexes is required to deliver and localize mitochondria to appropriate positions. Defects in mitochondrial transport are associated with various neurological disorders without a detailed mechanistic information. In this study, we present evidence that dystrobrevin-binding protein 1 (dysbindin), a schizophrenia-associated factor, plays a critical role in axonal mitochondrial movement. We observed that mitochondrial movement was impaired in dysbindin knockout mouse neurons. Reduced mitochondrial motility caused by dysbindin deficiency decreased the density of mitochondria in the distal part of axons. Moreover, the transport and distribution of mitochondria were regulated by the association between dysbindin and p150 glued . Furthermore, altered mitochondrial distribution in axons led to disrupted calcium dynamics, showing abnormal calcium influx in presynaptic terminals. These data collectively suggest that dysbindin forms a functional complex with p150 glued that regulates axonal mitochondrial transport, thereby affecting presynaptic calcium homeostasis.
... Moreover, 5-HT was shown to accumulate at a high rate using both of these methods. Evidence supports a novel and important link between schizophrenia, GABA and glutamate alterations [40]. In addition, several ndings suggest a correlation between glutamate and GABA in subjects with ASD, which also indicated that the neurotransmitter contributed to brain development [41,42]. ...
Background: Multiple clinical genome-wide analysis identified that chromosome 16p13.11 is a hotspot associated with neuropsychiatric disorders such as autism, schizophrenia and epilepsy. Nodal modulator 1 (NOMO1), located on human chromosome 16p13.11, was considered as a candidate gene with neuropsychiatric disorders. However, it is unknown whether the nomo1 deficiency causes neurological abnormalities, and the molecular mechanisms and pathogenesis of the NOMO1 gene remain unclear. To study the effects of nomo1 deficiency on brain development and neuropsychiatric system, a nomo1 knockout zebrafish model was established.
Methods: We developed a viable vertebrate model of nomo1 loss-of-function using CRISPR/Cas9 technology and characterized nomo1 mutant zebrafish. Phenotypic and functional studies of developing nomo1 mutant zebrafish, including morphological measurements, behavioral assays, and functional mechanistic analyses, were performed.
Results: Morphological differences in the phenotype of nomo1-/- zebrafish gradually became less noticeable during development, however, the enlarged interstitial spaces in midbrain and hindbrain were detected in nomo1 mutant zebrafish. Meanwhile, the nomo1 deficiency caused the change of expression levels in neurotransmitters of γ-aminobutyrate, glutamate and serotonin. Interestingly, the nomo1 loss-of-function zebrafish model exhibited social defects and repetitive behaviors in juvenile, which represented autism-like behaviors. The transcriptome analysis showed different gene expression patterns in mutant zebrafish at the genetic level. Further results revealed that the neuroactive drug PTZ recovered the decreased locomotor phenotype in larval mutant zebrafish.
Conclusions: In this study, we established a nomo1 vertebrate animal model using CRISPR/Cas9 gene editing approach. The loss-of-function of nomo1 displayed autism-like behaviors and altered levels of the γ-aminobutyrate, glutamate and serotonin in zebrafish, which provide evidence that nomo1 as a candidate gene for autism. The versatility of zebrafish model is contributed to studying NOMO1-related disorders and conducting drug screening in future.
Limitations: Further studies are needed to determine whether an intervention with a neuroactive drug in nomo1-/- zebrafish to alter the behavioral phenotype is applicable to the behavior of human patients.
... Existing attempts to use brain stimulation as a therapeutic intervention in SZ have largely focussed on stimulating DLPFC with mixed outcomes (Kumar et al., 2020;Lett et al., 2014). The evidence for PFC stimulation sites in SZ is supported by its abnormal activation during cognitive control (Callicott et al., 2003;Cannon et al., 2005), its disrupted connectivity profile (Fornito et al., 2011;Meyer-Lindenberg et al., 2001) and neurotransmitter regulation (Lewis and Moghaddam, 2006). Our data-driven simulation complements these observations by 15 . ...
Cognitive dysfunction is a core feature of many brain disorders such as schizophrenia (SZ), and has been linked to both aberrant brain functional connectivity (FC) and aberrant cognitive brain activations. We propose that aberrant network activity flow over FC pathways leads to altered cognitive activations that produce cognitive dysfunction in SZ. We tested this hypothesis using activity flow mapping - an approach that models the movement of task-related activity between brain regions as a function of FC. Using fMRI data from SZ individuals and healthy controls during a working memory task, we found that activity flow models accurately predict aberrant cognitive activations across multiple brain networks. Within the same framework, we simulated a connectivity-based clinical intervention, predicting specific treatments that normalized brain activations and behavior in independent patients. Our results suggest that dysfunctional task-evoked activity flow is a large-scale network mechanism contributing to the emergence of cognitive dysfunction in SZ.
... Our results fit with studies that found GABAergic channels to play a prominent role in generating gamma oscillations 29 and that gamma oscillation variability reflects differences resting in GABA concentration measured with MR spectroscopy 30 . This follows a long line of work where PING and similar circuit mechanisms have been used to explain the generation of gamma oscillations [31][32][33] . Also, they confirm results we obtained earlier using different models and statistical analyses. ...
Neural activity is organized at multiple scales, ranging from the cellular to the whole brain level. Connecting neural dynamics at different scales is important for understanding brain pathology. Neurological diseases and disorders arise from interactions between factors that are expressed in multiple scales. Here, we suggest a new way to link microscopic and macroscopic dynamics through combinations of computational models. This exploits results from statistical decision theory and Bayesian inference. To validate our approach, we used two independent MEG datasets. In both, we found that variability in visually induced oscillations recorded from different people in simple visual perception tasks resulted from differences in the level of inhibition specific to deep cortical layers. This suggests differences in feedback to sensory areas and each subject’s hypotheses about sensations due to differences in their prior experience. Our approach provides a new link between non-invasive brain imaging data, laminar dynamics and top-down control.
... Cognitive deficits are the core symptoms of schizophrenia (Barch and Ceaser, 2012;Foussias and Remington, 2010), and its biological mechanism is still far from solved. Numerous studies indicate that the abnormalities of multiple systems, such as the inflammatory system (Ribeiro-Santos et al., 2014), dopaminergic system (Cohen and Servan-Schreiber, 1993), glutamatergic system (Lewis and Moghaddam, 2006), etc., in schizophrenia contribute to cognitive deficits. Therefore, the cognitive deficits in patients with schizophrenia is an outcome of the interaction of multiple systems. ...
Dopaminergic and inflammatory systems have been proven to play an important role in the cognitive deficits of schizophrenia. Although increasing evidence indicates two systems have strong interaction, the relevant research on this interaction is still limited. Catechol-o-methyltransferase (COMT) and Interleukin-10 (IL-10) play critical functions in dopaminergic and inflammatory systems respectively, and their genetic polymorphisms are both associated with cognitive function. However, the interactive effect of their genetic polymorphisms has not been investigated. In this study, COMT Val158Met (rs4680) and IL-10 -592A/C (rs1800872) polymorphisms were measured in patients with chronic schizophrenia (n = 244) and healthy controls (n = 396), and their cognitive functions were assessed using the “Repeatable Battery for the Assessment of Neuropsychological Status” (RBANS). We found that IL-10 alone had no effect on cognitive function, while COMT affected language ability and interacted with the schizophrenia (case vs control) or sex in multiple RBANS indexes. Additionally, we found there was a significant interactive effect between IL-10 and COMT polymorphisms on multiple cognitive indexes of RBANS. In detail, the analysis showed that the IL-10 polymorphism had opposite effects on cognitive function in different COMT genotype carriers; meanwhile, the polymorphism of COMT only had a significant effect on cognitive function in IL-10 C carriers. And this interaction was more significant in schizophrenia than in controls. Our study discovered for the first time, there is an interactive effect between IL-10 and COMT genetic polymorphisms on cognitive function, which is valuable for further investigations and drug administrations associated with both systems.
... Although there are no comparable term human data, limited pathology and imaging studies in preterm infants have shown reductions in the numbers and complexity of cortical interneurons, refs [25,45] cortical interneuron migration, [7] interneuron neurogenesis, [46] and cortical GABAergic signaling [4]. Disruptions in interneuron function, resulting in reduced inhibitory control [47] and loss of the neurotrophic function of GABA, [48] are also implicated in many neurodevelopmental disorders including lissencephaly, intellectual disabilities, anxiety disorders, autism spectrum disorders, schizophrenia, and early life epilepsies [6,8,47,[49][50][51][52][53]. Similarly, experimental disturbances in interneuron survival and function during brain development in animals are associated with a range of learning and behavioral deficits [54,55]. ...
Perinatal hypoxia-ischemia is associated with disruption of cortical gamma-aminobutyric acid (GABA)ergic interneurons and their surrounding perineuronal nets, which may contribute to persisting neurological deficits. Blockade of connexin43 hemichannels using a mimetic peptide can alleviate seizures and injury after hypoxia-ischemia. In this study, we tested the hypothesis that connexin43 hemichannel blockade improves the integrity of cortical interneurons and perineuronal nets. Term-equivalent fetal sheep received 30 min of bilateral carotid artery occlusion, recovery for 90 min, followed by a 25-h intracerebroventricular infusion of vehicle or a mimetic peptide that blocks connexin hemichannels or by a sham ischemia + vehicle infusion. Brain tissues were stained for interneuronal markers or perineuronal nets. Cerebral ischemia was associated with loss of cortical interneurons and perineuronal nets. The mimetic peptide infusion reduced loss of glutamic acid decarboxylase-, calretinin-, and parvalbumin-expressing interneurons and perineuronal nets. The interneuron and perineuronal net densities were negatively correlated with total seizure burden after ischemia. These data suggest that the opening of connexin43 hemichannels after perinatal hypoxia-ischemia causes loss of cortical interneurons and perineuronal nets and that this exacerbates seizures. Connexin43 hemichannel blockade may be an effective strategy to attenuate seizures and may improve long-term neurological outcomes after perinatal hypoxia-ischemia.
... Genetic association studies verified the key role of DA in the etiology of ADHD [42]. Evidence supports a novel and important link between schizophrenia, γ-aminobutyrate (GABA) and glutamate alterations [43]. In our study, neurotransmitter metabolism analysis also provide evidence of the relationship between nomo1 deficiency and social defects. ...
Background: Clinical genome-wide analysis identified NOMO1 in human chromosome 16p13.11 as a candidate gene associated with neuropsychiatric disorders such as autism, schizophrenia and epilepsy. However, the important contributions underlying NOMO1 deficiency resulting in neuropsychiatric disorders is not understand, and the molecular and pathogenesis mechanisms of nomo1 gene are unclear. Therefore, it is necessary to construct animal models to systematically study the effects of nomo1 deficiency on neuropsychiatric system and explore pathogenic molecular mechanism of diseases.
Methods: We developed a viable vertebrate model of loss-of-function of nomo1 using CRISPR/Cas9 and studied the characterization of nomo1 mutant zebrafish. Phenotypic research was performed in developing nomo1 mutant zebrafish, including morphological measurements, behavioral tests, and functional mechanism analyses.
Results: The nomo1 loss-of-function zebrafish model accurately recapitulated key neuropsychiatric disorders traits. The mutant zebrafish showed decreased locomotion in the larval stage (7 dpf), increased spontaneous movement in infancy (15 dpf and 30 dpf), and social defects and repetitive behaviors in adolescence (2 mpf). More importantly, we demonstrated that these behavioral phenotypes stem from abnormal brain structure and neurotransmitter metabolism. Transcriptome analysis provided insights for studying the functional mechanism of nomo1 pathogenesis. Further results revealed that the neuroactive drug PTZ recovered the decreased locomotion phenotype in larval zebrafish, which provides functional basis for the exploration of drug sensitivity and intervention in behavioral phenotypes of nomo1 mutant zebrafish.
Conclusion: This study firstly reveal the functional evidence that loss-of-function of nomo1 elicits neuropsychiatric disorders, and emphasize the relationship between nomo1 deficiency and neuropsychiatric disorders from the perspectives of behavioral phenotypes, brain development, and neurotransmitter metabolism.
Limitation: The behavioral phenotype intervention of neuroactive drug in nomo1-/-zebrafish can be directly translated to the behavior of human associated diseases need further study.
... Studies on glutamatergic and GABAergic neurotransmission point to a possible role in the pathophysiology of schizophrenia [8][9][10][11][12] with hypofunction of the N-methyl-D-aspartate glutamate receptor and consequently aberrant glutamate release in target regions as a central theory [8,13,14]. An increasing amount of research is likewise investigating whether glutamate and gamma-aminobutyric acid (GABA) abnormalities are present prior to the development of frank psychotic symptoms [8,11,15,16]. ...
Background.:
Cerebral glutamate and gamma-aminobutyric acid (GABA) levels might predict clinical outcome in individuals at ultrahigh risk (UHR) for psychosis but have previously primarily been investigated in smaller cohorts. We aimed to study whether baseline levels of glutamate and GABA in anterior cingulate cortex (ACC) and glutamate in thalamus could predict remission status and whether baseline metabolites differed in the remission versus the nonremission group. We also investigated the relationship between baseline metabolite levels and severity of clinical symptoms, functional outcome, and cognitive deficits at follow-up.
Methods.:
About 124 UHR individuals were recruited at baseline. In this, 74 UHR individuals were clinically and cognitively assessed after 12 months, while remission status was available for 81 (25 remission/56 nonremission). Glutamate and GABA levels were assessed at baseline using 3 T proton magnetic resonance spectroscopy. Psychopathology, symptom severity, and remission were assessed with the Comprehensive Assessment of At-Risk Mental States and Clinical Global Impression and functional outcome with the Social and Occupational Functioning Assessment Scale. Cognitive function was estimated with the Cambridge Neuropsychological Test Automated Battery.
Results.:
There were no differences between baseline glutamate and GABA levels in subjects in the nonremission group compared with the remission group, and baseline metabolites could not predict remission status. However, higher baseline levels of GABA in ACC were associated with clinical global improvement (r = -0.34, N = 51, p = 0.01) in an explorative analysis.
Conclusions.:
The variety in findings across studies suggests a probable multifactorial influence on clinical outcome in UHR individuals. Future studies should combine multimodal approaches to attempt prediction of long-term outcome.
Schizophrenia (SZ) is a multifactorial disorder characterized by volume reduction in gray and white matter, oxidative stress, neuroinflammation, altered neurotransmission, as well as molecular deficiencies such as punctual mutation in Disrupted-in-Schizophrenia 1 protein. In this regard, it is essential to understand the underlying molecular disturbances to determine the pathophysiological mechanisms of the disease. The signaling pathways activated by G protein-coupled receptors (GPCRs) are key molecular signaling pathways altered in SZ. Convenient models need to be designed and validated to study these processes and mechanisms at the cellular level. Cultured olfactory stem cells are used to investigate neural molecular and cellular alterations related to the pathophysiology of SZ. Multipotent human olfactory stem cells are undifferentiated and express GPCRs involved in numerous physiological functions such as proliferation, differentiation and bioenergetics. The use of olfactory stem cells obtained from patients with SZ may identify alterations in GPCR signaling that underlie dysfunctional processes in both undifferentiated and specialized neurons or derived neuroglia. The present review aimed to analyze the role of GPCRs and their signaling in the pathophysiology of SZ. Culture of olfactory epithelial cells constitutes a suitable model to study SZ and other psychiatric disorders at the cellular level.
Although the precise mechanisms and pathways of schizophrenia remain something of a mystery, there is little dispute that cognitive deficits present as some of the clearest and most debilitating symptoms of the disease. This book describes the characteristics of cognitive deficits in schizophrenia, functional implications, the course of impairments, the genetic and biological contributions and reviews management options, including neuropsychological, psychological and pharmacological techniques. Chapters are written by leading experts in the field, in an accessible and highly informative style, ensuring the content is clinically relevant. State-of-the-art information about new developments in the treatment of related features of the illness, such as disability, is provided. The wide ranging focus of this volume will appeal to clinicians and academic researchers working with patients impaired by severe mental illness.
Although the precise mechanisms and pathways of schizophrenia remain something of a mystery, there is little dispute that cognitive deficits present as some of the clearest and most debilitating symptoms of the disease. This book describes the characteristics of cognitive deficits in schizophrenia, functional implications, the course of impairments, the genetic and biological contributions and reviews management options, including neuropsychological, psychological and pharmacological techniques. Chapters are written by leading experts in the field, in an accessible and highly informative style, ensuring the content is clinically relevant. State-of-the-art information about new developments in the treatment of related features of the illness, such as disability, is provided. The wide ranging focus of this volume will appeal to clinicians and academic researchers working with patients impaired by severe mental illness.
Although the precise mechanisms and pathways of schizophrenia remain something of a mystery, there is little dispute that cognitive deficits present as some of the clearest and most debilitating symptoms of the disease. This book describes the characteristics of cognitive deficits in schizophrenia, functional implications, the course of impairments, the genetic and biological contributions and reviews management options, including neuropsychological, psychological and pharmacological techniques. Chapters are written by leading experts in the field, in an accessible and highly informative style, ensuring the content is clinically relevant. State-of-the-art information about new developments in the treatment of related features of the illness, such as disability, is provided. The wide ranging focus of this volume will appeal to clinicians and academic researchers working with patients impaired by severe mental illness.
Although the precise mechanisms and pathways of schizophrenia remain something of a mystery, there is little dispute that cognitive deficits present as some of the clearest and most debilitating symptoms of the disease. This book describes the characteristics of cognitive deficits in schizophrenia, functional implications, the course of impairments, the genetic and biological contributions and reviews management options, including neuropsychological, psychological and pharmacological techniques. Chapters are written by leading experts in the field, in an accessible and highly informative style, ensuring the content is clinically relevant. State-of-the-art information about new developments in the treatment of related features of the illness, such as disability, is provided. The wide ranging focus of this volume will appeal to clinicians and academic researchers working with patients impaired by severe mental illness.
Although the precise mechanisms and pathways of schizophrenia remain something of a mystery, there is little dispute that cognitive deficits present as some of the clearest and most debilitating symptoms of the disease. This book describes the characteristics of cognitive deficits in schizophrenia, functional implications, the course of impairments, the genetic and biological contributions and reviews management options, including neuropsychological, psychological and pharmacological techniques. Chapters are written by leading experts in the field, in an accessible and highly informative style, ensuring the content is clinically relevant. State-of-the-art information about new developments in the treatment of related features of the illness, such as disability, is provided. The wide ranging focus of this volume will appeal to clinicians and academic researchers working with patients impaired by severe mental illness.
Although the precise mechanisms and pathways of schizophrenia remain something of a mystery, there is little dispute that cognitive deficits present as some of the clearest and most debilitating symptoms of the disease. This book describes the characteristics of cognitive deficits in schizophrenia, functional implications, the course of impairments, the genetic and biological contributions and reviews management options, including neuropsychological, psychological and pharmacological techniques. Chapters are written by leading experts in the field, in an accessible and highly informative style, ensuring the content is clinically relevant. State-of-the-art information about new developments in the treatment of related features of the illness, such as disability, is provided. The wide ranging focus of this volume will appeal to clinicians and academic researchers working with patients impaired by severe mental illness.
Although the precise mechanisms and pathways of schizophrenia remain something of a mystery, there is little dispute that cognitive deficits present as some of the clearest and most debilitating symptoms of the disease. This book describes the characteristics of cognitive deficits in schizophrenia, functional implications, the course of impairments, the genetic and biological contributions and reviews management options, including neuropsychological, psychological and pharmacological techniques. Chapters are written by leading experts in the field, in an accessible and highly informative style, ensuring the content is clinically relevant. State-of-the-art information about new developments in the treatment of related features of the illness, such as disability, is provided. The wide ranging focus of this volume will appeal to clinicians and academic researchers working with patients impaired by severe mental illness.
Schizophrenia (SZ) is a chronic and devastating mental illness that affects around 20 million individuals worldwide. Cognitive deficits and structural and functional changes of the brain, abnormalities of brain ECM components, chronic neuroinflammation, and devastating clinical manifestation during SZ are likely etiological factors shown by affected individuals. However, the pathophysiological events associated with multiple regulatory pathways involved in the brain of this complex disorder are still unclear. This study aimed to develop a pipeline based on bioinformatics and machine learning approaches for identifying potential therapeutic targets involving possible biological mechanisms from SZ patients and healthy volunteers. 420 overlapping DEGs from three RNA-seq datasets were identified. GO, and pathways analysis showed several biological mechanisms enriched by the commonly shared DEGs, including ECM organization, collagen fibril organization, integrin signaling pathway, inflammation mediated by chemokines and cytokines signaling pathway, and GABA-B receptor II and IL4 mediated signaling. 15 hub genes (FN1, COL1A1, COL3A1, COL1A2, COL5A1, COL2A1, COL6A2, COL6A3, MMP2, THBS1, DCN, LUM, HLA-A, HLA-C, and FBN1) were discovered by comprehensive analysis, which was mainly involved in the ECM organization and inflammatory signaling pathway. Furthermore, the miRNA target of the hub genes was analyzed with the random-forest-based approach software miRTarBase. In addition, the transcriptional factors and protein kinases regulating overlapping DEGs in SZ, namely, SUZ12, EZH2, TRIM28, TP53, EGR1, CSNK2A1, GSK3B, CDK1, and MAPK14, were also identified. The results point to a new understanding that the hub genes (fibronectin 1, collagen, matrix metalloproteinase-2, and lumican) in the ECM organization and inflammatory signaling pathways may be involved in the SZ occurrence and pathogenesis.
Disturbance in synaptic excitatory and inhibitory (E/I) transmission in the prefrontal cortex is considered a critical factor for cognitive dysfunction, a core symptom in schizophrenia. However, the cortical network pathophysiology induced by E/I imbalance is not well characterized, and an effective therapeutic strategy is lacking. In this study, we simulated imbalanced cortical network by using mice with parvalbumin neuron (PV) specific knockout of GluA1 (AMPA receptor subunit 1) (Gria1-PV KO) as an experimental model. Applying high-content confocal imaging and electrophysiological recordings in the medial prefrontal cortex (mPFC), we found structural and functional alterations in the local network of Gria1-PV KO mice. Additionally, we applied electroencephalography (EEG) to assess potential deficits in mismatch negativity (MMN), the standard readout in the clinic for measuring deviance detection and sensory information processing. Gria1-PV KO animals exhibited abnormal theta oscillation and MMN, which is consistent with clinical findings in cognitively impaired patients. Remarkably, we demonstrated that the glycine transporter 1 (GlyT1) inhibitor, Bitopertin, ameliorates E/I imbalance, hyperexcitability, and sensory processing malfunction in Gria1-PV KO mice. Our results suggest that PV-specific deletion of GluA1 might be an experimental approach for back translating the E/I imbalance observed in schizophrenic patients. Our work offers a systematic workflow to understand the effect of GlyT1 inhibition in restoring cortical network activity from single cells to local brain circuitry. This study highlights that selectively boosting NMDA receptor-mediated excitatory drive to enhance the network inhibitory transmission from interneurons to pyramidal neurons is a potential therapeutic strategy for restoring E/I imbalance-associated cognitive-related abnormality.
Psychosis involves changes in GABAergic and glutamatergic neurotransmission in auditory cortex that could be important for understanding sensory deficits and symptoms of psychosis. However, it is currently unclear whether such deficits are present in participants at clinical high-risk for psychosis (CHR-P) and whether they are associated with clinical outcomes. Magnetic Resonance Spectroscopy (MEGAPRESS, 1H-MRS at 3 Tesla) was used to estimate GABA, glutamate, and glutamate-plus-glutamine (Glx) levels in auditory cortex in a large sample of CHR-P (n = 99), CHR-N (clinical high-risk negative, n = 32), and 45 healthy controls. Examined were group differences in metabolite concentrations as well as relationships with clinical symptoms, general cognition, and 1-year follow-up clinical and general functioning in the CHR-P group. Results showed a marginal (p = 0.039) main group effect only for Glx, but not for GABA and glutamate concentrations, and only in left, not right, auditory cortex. This effect did not survive multiple comparison correction, however. Exploratory post-hoc tests revealed that there were significantly lower Glx levels (p = 0.029, uncorrected) in the CHR-P compared to the CHR-N group, but not relative to healthy controls (p = 0.058, uncorrected). Glx levels correlated with the severity of perceptual abnormalities and disorganized speech scores. However, in the CHR-P group, Glx levels did not predict clinical or functional outcomes. Accordingly, the findings from the present study suggest that MRS-measured GABA, glutamate and Glx levels in auditory cortex of CHR-P individuals are largely intact.
Background and Purpose
Dysregulation of dopaminergic transmission combined with transient hypofunction of N‐methyl‐d‐aspartate receptors (NMDARs) is a key mechanism that may underlie cognitive symptoms of schizophrenia.
Experimental Approach
Therefore, we aimed to identify electrophysiologic alterations in animals neonatally treated with the NMDA receptor antagonist, MK‐801, or with saline solution.
Key Results
Patch‐clamp whole‐cell recordings from MK‐801‐treated animals revealed altered passive and active electrophysiologic properties compared with CA1 pyramidal cells from saline‐treated animals, including up‐regulation of the K⁺ inward‐rectifier conductance and fast‐inactivating and slow/non‐inactivating K⁺ currents. Up‐regulation of these membrane ionic currents reduced the overall excitability and altered the firing properties of CA1 pyramidal cells. We also explored the capability of cells treated with MK‐801 to express intrinsic excitability potentiation, a non‐synaptic form of hippocampal plasticity associated with cognition and memory formation. CA1 pyramidal cells from animals treated with MK‐801 were unable to convey intrinsic excitability potentiation and had blunted synaptic potentiation. Furthermore, MK‐801‐treated animals also exhibited reduced cognitive performance in the Barnes maze task. Notably, activation of D1/D5 receptors with SKF‐38,393 partially restored electrophysiologic alterations caused by neonatal treatment with MK‐801.
Conclusion and Implications
Our results offer a molecular and mechanistic explanation based on dysregulation of glutamatergic transmission, in addition to dopaminergic transmission, that may contribute to the understanding of the cognitive deterioration associated with schizophrenia.
Ketamine is a dissociative anesthetic and a non-competitive NMDAR antagonist. At subanesthetic dose, ketamine can relieve pain and work as a fast-acting antidepressant, but the underlying molecular mechanism remains elusive. This study aimed to investigate the mode of action underlying the effects of acute subanesthetic ketamine treatment by bioinformatics analyses of miRNAs in the medial prefrontal cortex of male C57BL/6J mice. Gene Ontology and KEGG pathway analyses of the genes putatively targeted by ketamine-responsive prefrontal miRNAs revealed that acute subanesthetic ketamine modifies ubiquitin-mediated proteolysis. Validation analysis suggested that miR-148a-3p and miR-128-3p are the main players responsible for the subanesthetic ketamine-mediated alteration of ubiquitin-mediated proteolysis through varied regulation of ubiquitin ligases E2 and E3. Collectively, our data imply that the prefrontal miRNA-dependent modulation of ubiquitin-mediated proteolysis is at least partially involved in the mode of action by acute subanesthetic ketamine treatment.
Schizophrenia is a severe psychiatric disorder characterized by emotional, behavioral and cognitive disturbances, and the treatment of schizophrenia is often complicated by noncompliance and pharmacoresistance. The search for the pathophysiological mechanisms underlying schizophrenia has resulted in the proposal of several hypotheses to explain the impacts of environmental, genetic, neurodevelopmental, immune and inflammatory factors on disease onset and progression. This review discusses the newest insights into the pathophysiology of and risk factors for schizophrenia and notes novel approaches in antipsychotic treatment and potential diagnostic and theranostic biomarkers. The current hypotheses focusing on neuromediators (dopamine, glutamate, and serotonin), neuroinflammation, the cannabinoid hypothesis, the gut-brain axis model, and oxidative stress are summarized. Key genetic features, including small nucleotide polymorphisms, copy number variations, microdeletions, mutations and epigenetic changes, are highlighted. Current pharmacotherapy of schizophrenia relies mostly on dopaminergic and serotonergic antagonists/partial agonists, but new findings in the pathophysiology of schizophrenia have allowed the expansion of novel approaches in pharmacotherapy and the establishment of more reliable biomarkers. Substances with promising results in preclinical and clinical studies include lumateperone, pimavanserin, xanomeline, roluperidone, agonists of trace amine-associated receptor 1, inhibitors of glycine transporters, AMPA allosteric modulators, mGLUR2-3 agonists, D-amino acid oxidase inhibitors and cannabidiol. The use of anti-inflammatory agents as an add-on therapy is mentioned.
Introduction
Schizophrenia is a neuropsychiatric disorder that affects approximately 1% of individuals worldwide. There are no available medications to treat cognitive impairment in this patient population currently. Preclinical evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve cognitive function. There is a need to evaluate how GLP-1RAs alter specific domains of cognition and whether they will be of therapeutic benefit in individuals with schizophrenia.
Areas covered
This paper summarises the effects of GLP-1RAs on metabolic processes in the brain and how these mechanisms relate to improved cognitive function. We provide an overview of preclinical studies that demonstrate GLP-1RAs improve cognition and comment on their potential therapeutic benefit in individuals with schizophrenia.
Expert Opinion
To understand the benefits of GLP-1RAs in individuals with schizophrenia, further preclinical research with rodent models relevant to schizophrenia symptomology are needed. Moreover, preclinical studies must focus on using a wider range of behavioral assays to understand whether important aspects of cognition such as executive function, attention, and goal-directed behavior are improved using GLP-1RAs. Further research into the specific mechanisms of how GLP-1RAs affect cognitive function and their interactions with antipsychotic medication commonly prescribed is necessary.
Central chemoreception is an important mechanism by which changes in tissue CO 2 /H ⁺ regulate breathing, and the Locus coeruleus (LC) is one of many putative central chemoreceptor sites. Here, we studied the contribution of LC glutamatergic receptors on ventilatory, cardiovascular and thermal responses to hypercapnia. To this end, we measured pulmonary ventilation (VE), body temperatures (Tb), mean arterial pressure (MAP) and heart rate (fH) of male Wistar rats before and after microinjection of Kynurenic Acid (KY, an ionotropic glutamate receptors antagonist, 10 mM) or α‐methyl‐4‐carboxyphenylglycine (MCPG, a metabotropic glutamate receptor antagonist, 10 ηM) unilateraly into the LC, followed by 60 minutes of air or hypercapnia exposure (7% CO 2 ). Ventilatory response to hypercapnia was higher in animals treated with KY intra‐LC (1899 ± 83 mL kg ⁻¹ min ⁻¹ ) compared to the control group (1141 ± 64 mL kg ⁻¹ min ⁻¹ ; P < 0.01). However, the MCPG treatment within the LC had no effect on the hypercapnia‐induced hyperpnea. The cardiovascular and thermal control were not affected by hypercapnia or by the injection of KY and MCPG in the LC. These data suggest that the glutamate acting on ionotropic but not metabotropic receptors in the LC exerts an inibitory modulation of hypercapnia‐induced hyperpnea.
Financial support: FAPESP, CNPq, PROPe.
Although the molecular underpinnings of schizophrenia (SZ) are still incompletely understood, deficits in synaptic activity and neuronal connectivity have been identified as core pathomechanisms of SZ and other neuropsychiatric disorders. In this study, we generated induced pluripotent stem cell (iPSC) lines from skin fibroblasts from healthy donors and patients diagnosed with idiopathic SZ. We differentiated the human iPSC into cortical neurons both as adherent monolayers and as three-dimensional spheroids. RNA sequencing revealed little overlap in differentially expressed genes between 2D and 3D neuron cultures from SZ iPSC compared with controls. Notably, mRNA transcripts encoding dipeptidyl peptidase-like protein 6 (DPP6), an accessory subunit of Kv4.2 voltage-gated potassium channels, were massively increased in cortical neurons from SZ iPSC in the 2D and 3D model. Consistently, multielectrode array recordings and calcium imaging showed significantly decreased neuronal activity both in 2D and in 3D cultures from SZ neurons. To show a causal relationship, we treated iPSC-derived neurons in 2D cultures with lentiviral DPP6 shRNA vectors and the Kv4.2 channel blocker AmmTx3, respectively. Both treatments successfully reversed neuronal hypoexcitability and hypoactivity in cortical neurons from SZ iPSC. Our data highlight a contribution of DPP6 and Kv4.2 to the deficit in neurotransmission in an iPSC model for SZ, which may be of therapeutic relevance for a subset of SZ patients.
Ultra-high field proton magnetic resonance spectroscopy (¹HMRS) offers a unique opportunity to measure the concentration of neurometabolites implicated in psychosis (PSY). The extant 7 T ¹HMRS literature measuring glutamate-associated neurometabolites in the brain in PSY in vivo is small, but a comprehensive, quantitative summary of these data can offer insight and guidance to this emerging field. This meta-analysis examines proton spectroscopy (¹HMRS) measures of glutamate (Glu), glutamine (Gln), glutamate+glutamine (Glx), gamma aminobutyric acid (GABA), and glutathione (GSH) across 255 individuals with PSY (121 first episode) and 293 healthy comparison participants (HC). While all five neurometabolites were lower in PSY as compared to HC, only Glu (Cohen's d = −0.18) and GSH (Cohen's d = −0.21) concentrations were significantly lower in PSY, whereas concentrations of Gln, Glx, and GABA did not significantly differ between groups. Notably, ¹HMRS methodological choices and sample demographic characteristics did not impact study-specific effect sizes for PSY-related Glu or GSH differences. This review thus provides further evidence of neurometabolite dysfunction in first episode and chronic PSY, and thereby suggests that Glu and GSH abnormalities may additionally play a role in more incipient stages of the disorder: in clinical high risk stages. Additional 7 T neurochemical imaging studies in larger, longitudinal, and unmedicated samples and in youth at risk for developing psychosis are needed. Such studies will be critical for elucidating the neurodevelopmental and clinical time course of PSY-related neurometabolite alterations, and for assessing the potential for implicated metabolites to serve as druggable targets for decreasing PSY risk.
The present study was performed to assess the role of excitatory amino acid and dopamine receptors on associative functions of the prefrontal cortex (PFC) of the rat. Spatial delayed alternation was used as a PFC-sensitive cognitive task. In addition, in vivo microdialysis was used to assess the release of dopamine in the PFC. The noncompetitive NMDA antagonists ketamine (10-30 mg/kg) and MK-801 (0.1 and 0.5 mg/kg) dose-dependently impaired the spatial delayed alternation performance compared with the saline-treated control group. Administration of the dopamine antagonists raclopride (0.1 and 0.5 mg/kg), SCH-23390 (0.1 mg/kg), or haloperidol (0.1 mg/kg) was without a significant effect. However, haloperidol and raclopride (but not SCH-23390) reversed the disruptive effect of 30 mg/kg ketamine on spatial delayed alternation performance. Microdialysis studies revealed that this dose of ketamine preferentially increased the release of dopamine in the PFC compared with the striatum. These findings indicate that attenuation of glutamatergic neurotransmission at the NMDA receptor impairs PFC-dependent cognitive functions. Furthermore, activation of dopamine neurotransmission contributes, at least in part, to this impairment.
In the primate cerebral cortex, morphologically and functionally diverse classes of local circuit neurons containing the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) differentially regulate the activity of pyramidal cells, the principal type of excitatory output neurons. In schizophrenia, GABA neurotransmission in the prefrontal cortex (PFC) appears to be disturbed but whether specific populations of GABA neurons are affected is not known. The chandelier class of GABA neurons are of particular interest because their axon terminals, which form distinctive arrays termed "cartridges," provide inhibitory input exclusively to the axon initial segment of pyramidal cells. Thus, chandelier cells are positioned to powerfully regulate the excitatory output of pyramidal neurons and, consequently, to substantially affect the patterns of neuronal activity within the PFC. In this study, an antibody directed against the GABA membrane transporter GAT-1 was used to label GABA axon terminals in postmortem human brains. The relative density of GAT-1-immunoreactive axon cartridges furnished by chandelier neurons was decreased by 40% in the PFC of schizophrenic subjects compared with matched groups of normal control and nonschizophrenic psychiatric subjects. In contrast, markers of the axon terminals of other populations of GABA neurons were not altered in the schizophrenic subjects. Furthermore, the density of GAT-1-immunoreactive axon cartridges was not altered in psychiatric subjects who had been treated with antipsychotic medications. The changes in GAT-1-immunoreactive axon cartridges of chandelier neurons in schizophrenia are likely to reflect altered information processing within the PFC and in its output connections to other brain regions and could contribute to the cognitive impairments seen in this disorder.
Cognitive deficits are a fundamental feature of the psychopathology of schizophrenia. Yet the effect of treatment on this dimension of the illness has been unclear. Atypical antipsychotic medications have been reported to reduce the neurocognitive impairment associated with schizophrenia. However, studies of the pattern and degree of cognitive improvement with these compounds have been methodologically limited and have produced variable results, and few findings have been replicated. To clarify our understanding of the effects of atypical antipsychotic drugs on neurocognitive deficits in patients with schizophrenia, we have (1) reported on newly established standards for research design in studies of treatment effects on cognitive function in schizophrenia, (2) reviewed the literature on this topic and determined the extent to which 15 studies on the effect of atypical antipsychotics met these standards, (3) performed a meta-analysis of the 15 studies, which suggested general cognitive enhancement with atypical antipsychotics, and (4) described the pharmacological profile of these agents and considered the pharmacological basis for their effects on neurocognition. Finally, we suggest directions for the development of new therapeutic strategies.
This study sought to determine whether thought disorder induced in healthy volunteers by the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine resembles the thought disorder found in patients with schizophrenia.
The Scale for the Assessment of Thought, Language, and Communication was used to assess thought disorder in healthy volunteers (N = 10) who received subanesthetic doses of ketamine and in a group of clinically stable inpatients with schizophrenia (N = 15) who did not receive ketamine.
Mean scores on the Scale for the Assessment of Thought, Language, and Communication for patients with schizophrenia and healthy volunteers receiving ketamine did not differ significantly. Moreover, three of the four highest rated test items in both groups were the same.
These data suggest that ketamine-induced thought disorder in healthy volunteers is not dissimilar to the thought disorder in patients with schizophrenia and provide support for the involvement of the NMDA receptor in a cardinal symptom of schizophrenia.
The least known aspect of the functional architecture of hippocampal microcircuits is the quantitative distribution of synaptic inputs of identified cell classes. The complete dendritic trees of functionally distinct interneuron types containing parvalbumin (PV), calbindin D 28k (CB), or calretinin (CR) were reconstructed at the light microscopic level to describe their geometry, total length, and laminar distribution. Serial electron microscopic reconstruction and postembedding GABA immunostaining was then used to determine the density of GABA-negative asymmetrical (excitatory) and GABA-positive symmetrical (inhibitory) synaptic inputs on their dendrites, somata, and axon initial segments. The total convergence and the distribution of excitatory and inhibitory inputs were then calculated using the light and electron microscopic data sets.
The three populations showed characteristic differences in dendritic morphology and in the density and distribution of afferent synapses. PV cells possessed the most extensive dendritic tree (4300 μm) and the thickest dendrites. CR cells had the smallest dendritic tree (2500 μm) and the thinnest shafts. The density of inputs as well as the total number of excitatory plus inhibitory synapses was several times higher on PV cells (on average, 16,294) than on CB (3839) or CR (2186) cells. The ratio of GABAergic inputs was significantly higher on CB (29.4%) and CR (20.71%) cells than on PV cells (6.4%). The density of inhibitory terminals was higher in the perisomatic region than on the distal dendrites.
These anatomical data are essential to understand the distinct behavior and role of these interneuron types during hippocampal activity patterns and represent fundamental information for modeling studies.
Local circuit neurons in the dorsolateral prefrontal cortex (dPFC) of monkeys have been implicated in the cellular basis of working memory. To further elucidate the role of inhibition in spatial tuning, we iontophoresed bicuculline methiodide (BMI) onto functionally characterized neurons in the dPFC of monkeys performing an oculomotor delayed response task. This GABA(A) blockade revealed that both putative interneurons and pyramidal cells possess significant inhibitory tone in the awake, behaving monkey. In addition, BMI application primarily resulted in the loss of previously extant spatial tuning in both cell types through reduction of both isodirectional and cross-directional inhibition. This tuning loss occurred in both the sensorimotor and mnemonic phases of the task, although the delay activity of prefrontal neurons appeared to be particularly affected. Finally, application of BMI also created significant spatial tuning in a sizable minority of units that were untuned in the control condition. Visual field analysis of such tuning suggests that it is likely caused by the unmasking of normally suppressed spatially tuned excitatory input. These findings provide the first direct evidence of directional inhibitory modulation of pyramidal cell and interneuron firing in both the mnemonic and sensorimotor phases of the working memory process, and they implicate a further role for GABAergic interneurons in the construction of spatial tuning in prefrontal cortex.
The dorsolateral prefrontal cortex has been implicated in both working memory and the pathophysiology of schizophrenia. A relationship among dorsolateral prefrontal cortex activity, working memory dysfunction, and symptoms in schizophrenia has not been firmly established, partly because of generalized cognitive impairments in patients and task complexity. Using tasks that parametrically manipulated working memory load, the authors tested three hypotheses: 1) patients with schizophrenia differ in prefrontal activity only when behavioral performance differentiates them from healthy comparison subjects, 2) dorsolateral prefrontal cortex dysfunction is associated with poorer task performance, and 3) dorsolateral prefrontal cortex dysfunction is associated with cognitive disorganization but not negative or positive symptoms.
Seventeen conventionally medicated patients with schizophrenia and 16 healthy comparison subjects underwent functional magnetic resonance imaging while performing multiple levels of the "n-back" sequential-letter working memory task.
Patients with schizophrenia showed a deficit in physiological activation of the right dorsolateral prefrontal cortex (Brodmann's area 46/9) in the context of normal task-dependent activity in other regions, but only under the condition that distinguished them from comparison subjects on task performance. Patients with greater dorsolateral prefrontal cortex dysfunction performed more poorly. Dorsolateral prefrontal cortex dysfunction was selectively associated with disorganization symptoms.
These results are consistent with the hypotheses that working memory dysfunction in patients with schizophrenia is caused by a disturbance of the dorsolateral prefrontal cortex and that this disturbance is selectively associated with cognitive disorganization. Further, the pattern of behavioral performance suggests that dorsolateral prefrontal cortex dysfunction does not reflect a deficit in the maintenance of stimulus representations per se but points to deficits in more associative components of working memory.
A combination of genetic susceptibility and environmental perturbations appear to be necessary for the expression of schizophrenia. In addition, the pathogenesis of the disease is hypothesized to be neurodevelopmental in nature based on reports of an excess of adverse events during the pre- and perinatal periods, the presence of cognitive and behavioral signs during childhood and adolescence, and the lack of evidence of a neurodegenerative process in most individuals with schizophrenia. Recent studies of neurodevelopmental mechanisms strongly suggest that no single gene or factor is responsible for driving a highly complex biological process. Together, these findings suggest that combinatorial genetic and environmental factors, which disturb a normal developmental course early in life, result in molecular and histogenic responses that cumulatively lead to different developmental trajectories and the clinical phenotype recognized as schizophrenia.
The glutamate system is involved in many aspects of neuronal synaptic strength and function during development and throughout life. Synapse formation in early brain development, synapse maintenance, and synaptic plasticity are all influenced by the glutamate system. The number of neurons and the number of their connections are determined by the activity of the glutamate system and its receptors. Malfunctions of the glutamate system affect neuroplasticity and can cause neuronal toxicity. In schizophrenia, many glutamate-regulated processes seem to be perturbed. Abnormal neuronal development, abnormal synaptic plasticity, and neurodegeneration have been proposed to be causal or contributing factors in schizophrenia. Interestingly, it seems that the glutamate system is dysregulated and that N-methyl-D-aspartate receptors operate at reduced activity. Here we discuss how the molecular aspects of glutamate malfunction can explain some of the neuropathology observed in schizophrenia, and how the available treatment intervenes through the glutamate system.
Numerous human imaging studies have revealed an absolute or relative metabolic hypofunction within the prefrontal cortex, thalamus and temporal lobes of schizophrenic patients. The former deficit correlates with cognitive deficits and negative symptoms, whereas the latter correlates with positive symptomologies. There is also general consensus that schizophrenia is associated with decreased parvalbumin expression in the prefrontal cortex. Since the drug phencyclidine can induce a psychosis resembling schizophrenia in humans, we have examined whether repeated phencyclidine (PCP) treatment to rats could produce similar metabolic and neurochemical deficits to those occurring in schizophrenia and whether these deficits could be modulated by antipsychotic drugs. We demonstrate here that chronic intermittent exposure to PCP (2.58 mg kg(-1) i.p.) elicits a metabolic hypofunction, as demonstrated by reductions in the rates of glucose utilization, within the prefrontal cortex, reticular nucleus of thalamus and auditory system, key structures displaying similar changes in schizophrenia. Moreover, chronic PCP treatment according to this regime also decreases parvalbumin mRNA expression in the rat prefrontal cortex and reticular nucleus of the thalamus. Chronic coadministration of haloperidol (1 mg kg(-1) day(-1)) or clozapine (20 mg kg(-1) day(-1)) with PCP did not modulate PCP-induced reductions in metabolic activity in the rat prefrontal cortex, but reversed deficits in the structures of the auditory system. Clozapine, but not haloperidol, reversed PCP-induced decreases in parvalbumin expression in prefrontal cortex GABAergic interneurons, whereas both drugs reversed the deficits in the reticular nucleus of the thalamus. These data provide important new information, which strengthen the validity of chronic PCP as a useful animal model of schizophrenia, when administered according to this protocol. Furthermore, we propose that reversal of PCP-induced reductions in parvalbumin expression in the prefrontal cortex may be a potential marker of atypical antipsychotic activity in relation to amelioration of cognitive deficits and negative symptoms of schizophrenia.
Markers of inhibitory neurotransmission are altered in the prefrontal cortex (PFC) of subjects with schizophrenia, and several lines of evidence suggest that these alterations may be most prominent in the subset of GABA-containing neurons that express the calcium-binding protein, parvalbumin (PV). To test this hypothesis, we evaluated the expression of mRNAs for PV, another calcium-binding protein, calretinin (CR), and glutamic acid decarboxylase (GAD67) in postmortem brain specimens from 15 pairs of subjects with schizophrenia and matched control subjects using single- and dual-label in situ hybridization. Signal intensity for PV mRNA expression in PFC area 9 was significantly decreased in the subjects with schizophrenia, predominantly in layers III and IV. Analysis at the cellular level revealed that this decrease was attributable principally to a reduction in PV mRNA expression per neuron rather than by a decreased density of PV mRNA-positive neurons. In contrast, the same measures of CR mRNA expression were not altered in schizophrenia. These findings were confirmed by findings from cDNA microarray studies using different probes. Across the subjects with schizophrenia, the decrease in neuronal PV mRNA expression was highly associated (r = 0.84) with the decrease in the density of neurons containing detectable levels of GAD67 mRNA. Furthermore, simultaneous detection of PV and GAD67 mRNAs revealed that in subjects with schizophrenia only 55% of PV mRNA-positive neurons had detectable levels of GAD67 mRNA. Given the critical role that PV-containing GABA neurons appear to play in regulating the cognitive functions mediated by the PFC, the selective alterations in gene expression in these neurons may contribute to the cognitive deficits characteristic of schizophrenia.
This study tested the hypothesis that impaired working memory is a core deficit underlying multiple neuropsychological deficits in schizophrenia patients.
The subjects were 27 men with stable chronic schizophrenia treated with atypical antipsychotics and 38 normal participants. They were assessed with a battery of neuropsychological tests. Verbal working memory was measured with the WAIS digit span tests, and the Dot Test was used to test spatial working memory.
In the patients, verbal working memory showed significant correlations with visual retention, visual orientation, simple motor function, visuomotor coordination, and executive function but not with memory for objects, memory for faces, recognition of facial emotions, or attention. Spatial working memory showed significant correlations with visual retention, visual orientation, memory for objects, memory for faces, and simple motor function but not attention, executive function, or visuomotor coordination. In the comparison group, no correlations between working memory and other neuropsychological functions were found.
These findings support the hypothesis that working memory is a core deficit in schizophrenia. The authors postulate that the lower capacity for verbal and spatial "on-line storage" is rate limiting in the performance of other cognitive functions. Executive functions rely critically on the phonetic loop, complex visual functions such as object and face memory rely on the spatial on-line storage system (visuospatial scratch pad), while other functions such as visual orientation depend critically on both capacities.
Numerous neuroimaging studies have examined the function of the dorsolateral prefrontal cortex in schizophrenia; although abnormalities usually are identified, it is unclear why some studies find too little activation and others too much. The authors' goal was to explore this phenomenon.
They used the N-back working memory task and functional magnetic resonance imaging at 3 T to examine a group of 14 patients with schizophrenia and a matched comparison group of 14 healthy subjects.
Patients' performance was significantly worse on the two-back working memory task than that of healthy subjects. However, there were areas within the dorsolateral prefrontal cortex of the patients that were more active and areas that were less active than those of the healthy subjects. When the groups were subdivided on the basis of performance on the working memory task into healthy subjects and patients with high or low performance, locales of greater prefrontal activation and locales of less activation were found in the high-performing patients but only locales of underactivation were found in the low-performing patients.
These findings suggest that patients with schizophrenia whose performance on the N-back working memory task is similar to that of healthy comparison subjects use greater prefrontal resources but achieve lower accuracy (i.e., inefficiency) and that other patients with schizophrenia fail to sustain the prefrontal network that processes the information, achieving even lower accuracy as a result. These findings add to other evidence that abnormalities of prefrontal cortical function in schizophrenia are not reducible to simply too much or too little activity but, rather, reflect a compromised neural strategy for handling information mediated by the dorsolateral prefrontal cortex.
Context processing is a cognitive construct associated with activity in the middle frontal gyrus. Schizophrenia-related deficits in context processing tasks have been associated with prefrontal cortical dysfunction. This study evaluated whether prefrontal cortical dysfunction related to context processing occurred in first-episode, never-medicated schizophrenia patients, whether this dysfunction also occurred in patients with nonschizophrenia psychosis, and whether this dysfunction was related to psychotic symptom expression.
A modified version of the AX continuous performance task was conducted during event-related functional magnetic resonance imaging in 18 never-medicated, first-episode schizophrenia patients, 12 never-medicated patients with first-episode nonschizophrenia psychosis, and 28 comparison participants without psychiatric disorder.
In-scanner measures of errors and interference reaction time showed that the schizophrenia patients had a specific deficit in context processing. Trials with greater context processing demands corresponded to activity in the middle frontal gyrus (Brodmann's area 9) in the comparison subjects and in the patients with nonschizophrenia psychosis, but not in the schizophrenia patients. Individual differences in prefrontal cortical dysfunction were associated with context processing measures and disorganization symptoms. The schizophrenia patients also showed increased activity in the anterior (Brodmann's area 10) and inferior prefrontal cortices (Brodmann's area 45/46) when they were maintaining context over a delay.
Prefrontal dysfunctions related to context processing were found only in schizophrenia patients early in the course of the illness, and these dysfunctions were related to disorganization symptoms. Instead of using context processing during a continuous performance task, schizophrenia patients may use an inefficient encoding and retrieval strategy.
Impairments in certain cognitive functions, such as working memory, are core features of schizophrenia. Convergent findings indicate that a deficiency in signalling through the TrkB neurotrophin receptor leads to reduced GABA (gamma-aminobutyric acid) synthesis in the parvalbumin-containing subpopulation of inhibitory GABA neurons in the dorsolateral prefrontal cortex of individuals with schizophrenia. Despite both pre- and postsynaptic compensatory responses, the resulting alteration in perisomatic inhibition of pyramidal neurons contributes to a diminished capacity for the gamma-frequency synchronized neuronal activity that is required for working memory function. These findings reveal specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.
Pharmacological manipulation of N-methyl-D-aspartate (NMDA) receptors may be critical for the treatment of many neurological and psychiatric disorders. Metabotropic glutamate (mGlu5) receptors are abundant in corticolimbic circuitry, where they modulate NMDA receptor-mediated signal transduction. Therefore, pharmacological manipulation of mGlu5 receptor may provide a treatment strategy for cognitive disorders that are associated with NMDA receptor dysfunction. We sought to determine whether the recently described molecular and cellular interactions between NMDA and mGlu5 receptors coregulate higher order behaviors. We examined the interaction of the selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and the use-dependent NMDA antagonist MK-801, on locomotion, stereotypy, working memory, instrumental learning, and corticolimbic dopamine release. MPEP, at 10 mg/kg, but not 3 mg/kg, impaired working memory and instrumental learning, transiently increased dopamine release in prefrontal cortex and nucleus accumbens, and augmented the effect of MK-801 on cortical dopamine release, locomotion, and stereotypy. Pretreatment with 3 mg/kg of MPEP enhanced the detrimental effects of MK-801 on cognition. These results demonstrate that an mGlu5 receptor antagonist can potentiate the motoric, cognitive, and dopaminergic effects of an NMDA receptor antagonist. Thus, mGlu5 receptors appear to play a major role in regulating NMDA receptor-dependent cognitive functions such as learning and working memory. By extension, these results suggest that pharmacological potentiation of mGlu5 receptors may ameliorate the cognitive and other behavioral abnormalities associated with NMDA receptor deficiency.
The cellular and synaptic localization of immunoreactivity for the N-methyl-D-aspartate (NMDA) receptor subunit, NMDAR1, was investigated in inferotemporal and prefrontal association neocortices of monkeys and humans. In all monkey association areas examined, the laminar distribution patterns of NMDAR1 immunoreactivity were similar, and characterized by predominant pyramidal-like neuronal labeling in layers II, III, V and VI and a dense neuropil labeling consisting of intensely stained puncta and fine-caliber processes present throughout layers I-III, and V-VI. Layer IV, in contrast, contained only very lightly immunostained neurons which mostly lacked extensive dendritic staining. The laminar distribution of NMDAR1 immunolabeling in human association cortex was similar to that observed in monkeys. Electron microscopy of monkey areas 46 and TE1 confirmed that intensely immunoreactive asymmetrical postsynaptic densities were present throughout all cell-dense layers of prefrontal and inferotemporal association cortex. Quantitative analyses of the laminar proportions of immunoreactive synapses demonstrated that in both areas examined, the percentages of immunolabeled synapses were mostly similar across superficial layers, layer IV and infragranular layers. Finally, quantitative double-labeling immunofluorescence for non-NMDA receptor subunits or calcium-binding proteins demonstrated that virtually all GluR2/3 or GluR5/6/7-immunoreactive neurons were also labeled for NMDAR1, while regionally-specific subsets of parvalbumin-, calbindin- and calretinin-immunoreactive neurons were co-labeled. These data indicate that in primate association cortex, NMDA receptors are heterogeneously distributed to subsets of functionally distinct types of neurons and subsets of excitatory synapses, suggesting a critical and highly specific role in mediating the activity of excitatory connectivity which converges on cortical association areas.
Markers of gamma-aminobutyric acid (GABA) neurotransmission seem to be altered in the prefrontal cortex (PFC) of subjects with schizophrenia. We sought to determine whether the expression of the messenger RNA (mRNA) for the synthesizing enzyme of GABA, glutamic acid decarboxylase67 (GAD67), is decreased in the PFC of subjects with schizophrenia, whether this change is present in all or only some GABA neurons, and whether long-term treatment with haloperidol decanoate contributes to altered GAD67 mRNA expression.
Tissue sections from 10 pairs of subjects with schizophrenia and control subjects and 4 pairs of haloperidol-treated and control monkeys were processed for in situ hybridization histochemical analysis with sulfur-35-labeled oligonucleotide probes for GAD67 mRNA and exposed to nuclear emulsion. Within each layer of PFC area 9, neurons expressing a detectable level of GAD67 mRNA were quantified for cell density and the relative level of mRNA expression per cell (grain density per neuron).
In subjects with schizophrenia, the density of labeled neurons was significantly (P<.05) decreased by 25% to 35% in cortical layers 3 to 5. In contrast, the mean grain density per labeled neuron did not differ across subject groups. Similar analyses in monkeys revealed no effect of long-term haloperidol treatment on either the density of the labeled neurons or the grain density per labeled neuron.
These findings indicate that in subjects with schizophrenia, GAD67 mRNA expression is relatively unaltered in most PFC GABA neurons but is reduced below a detectable level in a subset of GABA neurons. Altered GABA neurotransmission in this subset may contribute to PFC dysfunction in subjects with schizophrenia.
Within the prefrontal cortex of schizophrenic subjects, alterations in markers of gamma-aminobutyric acid (GABA) neurotransmission, including decreased immunoreactivity for the GABA membrane transporter GAT-1, may be most prominent in a subset of inhibitory neurons. In the present study, the authors sought to determine whether the alterations in GAT-1 protein could be attributed to a reduction in GAT-1 mRNA expression.
Tissue sections containing prefrontal cortex area 9 from 10 matched pairs of schizophrenic and comparison subjects were processed for in situ hybridization histochemistry with (35)S-oligonucleotide probes for GAT-1 mRNA.
In the schizophrenic subjects, the relative density of labeled neurons was 21%-33% lower in layers 1-5 of the prefrontal cortex but was unchanged in layer 6. In contrast, cellular levels of GAT-1 mRNA expression, as reflected in grain density per labeled neuron, did not differ by more than 11% between subject groups in any layer. These findings indicate that GAT-1 mRNA expression is relatively unaltered in the majority of prefrontal cortex GABA neurons in schizophrenic subjects but is reduced below a detectable level in a subset of GABA neurons. Furthermore, the magnitude and laminar pattern of these results were strikingly similar to those found in a previous study of mRNA expression for the synthesizing enzyme of GABA, glutamic acid decarboxylase(67), in the same subjects.
Both GABA synthesis and reuptake appear to be altered at the level of gene expression in a subset of GABA neurons, and the resulting changes in GABA neurotransmission may contribute to prefrontal cortex dysfunction in schizophrenia.
Patients with schizophrenia exhibit an exceedingly wide range of symptoms from a variety of domains. The cardinal features are abnormal ideas (such as delusions); abnormal perceptions (such as hallucinations); formal thought disorder (as evidenced by disorganized speech); motor, volitional, and behavioral disorders; and emotional disorders (such as affective flattening or inappropriateness). In addition to these diverse, and sometimes bizarre symptoms, it has become increasingly apparent that the disorder is, to variable degrees, accompanied by a broad spectrum of cognitive impairments. This review addresses the question of whether the cognitive deficits seen in schizophrenic patients are the core features of the disorder. In other words, we explore whether schizophrenia is best characterized by symptoms or cognitive deficits (we suggest the latter) and moreover, whether there is a specific cognitive deficit profile that may assist in diagnosis. First, we discuss what the cognitive deficits are. Then we address in turn the reality, frequency, predictive validity, specificity, course and susceptibility to neuroleptic effects of these cognitive impairments. In brief, we argue that various cognitive deficits are enduring features of the schizophrenia illness, that they are not state-related and are not specific to subtypes of the illness, and, more specifically, that working memory and attention are characteristically impaired in patients with schizophrenia, irrespective of their level of intelligence. Last, we conclude that problems in these cognitive domains are at the very core of the dysfunction in this disease.
CX516, a positive modulator of the glutamatergic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor, improves performance in tasks requiring learning and memory in animals. CX516 was added to clozapine in 4-week, placebo-controlled, dose-finding (N = 6) and fixed-dose (N = 13) trials. CX516 was tolerated well and was associated with moderate to large, between-group effect sizes compared with placebo, representing improvement in measures of attention and memory. These preliminary results suggest that CX516 and other "ampakines" hold promise for the treatment of schizophrenia.
In the prefrontal cortex of subjects with schizophrenia, markers of the synthesis and re-uptake of GABA appear to be selectively altered in a subset of interneurons that includes chandelier cells. Determining the effect of these disturbances in presynaptic GABA markers on inhibitory signaling requires knowledge of the status of GABA(A) receptors at the postsynaptic targets of chandelier cells, the axon initial segments (AIS) of pyramidal neurons. Because the alpha(2) subunit of the GABA(A) receptor is preferentially localized at pyramidal neuron AIS, we quantified alpha(2) subunit immunoreactive AIS in tissue sections containing prefrontal cortex area 46 from 14 matched triads of subjects with schizophrenia, subjects with major depression and control subjects. Systematic, random sampling revealed that the mean number of alpha(2)-labeled AIS per mm(2) in subjects with schizophrenia was significantly (P = 0.007) increased by 113% compared to control subjects and non-significantly increased compared to subjects with major depression. Furthermore, within subjects with schizophrenia, the density of alpha(2)-labeled AIS was negatively correlated (r = -0.49, P = 0.038) with the density of chandelier axon terminals immunoreactive for the GABA membrane transporter. These data suggest that GABA(A) receptors are up-regulated at pyramidal neuron AIS in response to deficient GABA neuro-transmission at chandelier axon terminals in schizophrenia. Thus, disturbances in inhibition at the chandelier neuron-pyramidal neuron synapse may be a critical component of prefrontal cortical dysfunction in schizophrenia.
We used L-(quinoxalin-6-ylcarbonyl)piperidine (CX516) (a modulator of the alpha-amino-3-hydroxy-5-methyl-4-isoxasole propionic acid (AMPA) receptor) as a sole agent in a double blind placebo-controlled design in a small series of patients with schizophrenia who were partially refractory to treatment with traditional neuroleptics. The study entailed weekly increments in doses of CX516, from 300 mg tid for week 1 up to 900 mg tid on week 4. Patients were followed with clinical ratings, neuropsychological testing, and were monitored for adverse events. Four patients received 2 to 4 weeks of CX516, two received placebo and two withdrew during the placebo phase. Adverse events associated with drug administration were transient and included leukopenia in one patient and elevation in liver enzymes in another. No clear improvement in psychosis or in cognition was observed over the course of the study. CX516 at the doses tested did not appear to yield dramatic effects as a sole agent, but inference from this study is limited.
In monkey prefrontal cortex (PFC), approximately 50% of the local axon terminals of pyramidal neurons form synapses with the dendritic shafts of GABA neurons. Subclasses of GABA neurons can be distinguished by the presence of different calcium-binding proteins. For example, in monkey PFC, parvalbumin (PV)-containing cells comprise approximately 25% of GABA neurons and are predominantly located in layers 3b-4, whereas calretinin (CR)-containing cells, which are present in greatest density in layers 2-3a, constitute 50% of GABA neurons. Consequently, in order to determine the cell class and laminar specificity of the dendritic targets of pyramidal neuron local axon collaterals in monkey PFC area 9, we conducted ultrastructural analyses of local axon terminals labeled with the anterograde tracer, biotinylated dextran amine, and dendrites immunoreactive (IR) for PV or CR. In layer 3b, the majority of the local axon terminals targeted PV-IR dendritic shafts, whereas CR-IR dendritic shafts were targeted infrequently. This differential targeting was also present in layers 2-3a, although it was less pronounced. In addition, PV-IR dendrites had a significantly greater density of excitatory inputs than did CR-IR dendrites. These findings indicate that PV-containing interneurons, which have a potent inhibitory effect on pyramidal neurons, are selectively targeted by the excitatory local axon terminals of supragranular pyramidal neurons in monkey PFC. These connections may provide the anatomical substrate for the coordinated activity of pyramidal neurons and fast-spiking GABA neurons during working memory.
The high heritability of schizophrenia has stimulated much work aimed at identifying susceptibility genes using positional genetics. However, difficulties in obtaining clear replicated linkages have led to the scepticism that such approaches would ever be successful. Fortunately, there are now signs of real progress. Several strong and well-established linkages have emerged. Three of the best-supported regions are 6p24-22, 1q21-22 and 13q32-34. In these cases, single studies achieved genome-wide significance at P<0.05 and suggestive positive findings have also been reported in other samples. The other promising regions include 8p21-22, 6q21-25, 22q11-12, 5q21-q33, 10p15-p11 and 1q42. The study of chromosomal abnormalities in schizophrenia has also added to the evidence for susceptibility loci at 22q11 and 1q42. Recently, evidence implicating individual genes within some of the linked regions has been reported and more importantly replicated. The weight of evidence now favours NRG1 and DTNBP1 as susceptibility loci, though work remains before we understand precisely how genetic variation at each locus confers susceptibility and protection. The evidence for catechol-O-methyl transferase, RGS4 and G72 is promising but not yet persuasive. While further replications remain the top priority, the respective contributions of each gene, relationships with aspects of the phenotype, the possibility of epistatic interactions between genes and functional interactions between the gene products will all need investigation. The ability of positional genetics to implicate novel genes and pathways will open up new vistas for neurobiological research, and all the signs are that it is now poised to deliver crucial insights into the nature of schizophrenia.
In vitro models of rhythms of cognitive relevance, such as gamma (30-80 Hz) and theta (5-12 Hz) rhythms in the hippocampus, demonstrate an absolute requirement for phasic inhibitory synaptic transmission. Such rhythms can occur transiently, of approximately 1 s duration, or persistently, lasting for many hours. In the latter case, stable patterns of interneuron output, and their postsynaptic consequences for pyramidal cell membrane potential, occur despite known constraints of synaptic habituation and potentiation. This review concentrates on recent in vitro evidence revealing a division of labour among different subclasses of interneurons with respect to the frequency of persistent rhythms, and the crucial dependence on gap-junction-mediated intercellular communication for the generation and maintenance of these rhythms.
Recent genetic linkage studies complement the existing evidence that implicates abnormalities in NMDA receptor-mediated neurotransmission in the pathophysiology of schizophrenia. At the same time, advances in our understanding of the complex mechanisms that modulate the function of NMDA receptors suggest several novel sites for pharmacological manipulation of these receptors. This presents exciting opportunities for rational rather than serendipitous discovery of therapeutics for schizophrenia.
Several lines of evidence implicate NMDA receptor dysfunction in the cognitive deficits of schizophrenia, suggesting that pharmacological manipulation of the NMDA receptor may be a feasible therapeutic strategy for treatment of these symptoms. Although direct manipulation of regulatory sites on the NMDA receptor is the most obvious approach for pharmacological intervention, targeting the G-protein coupled metabotropic glutamate (mGlu) receptors may be a more practical strategy for long-term regulation of abnormal glutamate neurotransmission. Heterogeneous distribution, both at structural and synaptic levels, of at least eight subtypes of mGlu receptors suggests that selective pharmacological manipulation of these receptors may modulate glutamatergic neurotransmission in a regionally and functionally distinct manner. Two promising targets for improving cognitive functions are mGlu5 or mGluR2/3 receptors, which can modulate the NMDA receptor-mediated signal transduction by pre- or postsynaptic mechanisms. Preclinical studies indicate that activation of these subtypes of mGlu receptors may be an effective strategy for reversing cognitive deficits resulting form reduced NMDA receptor mediated neurotransmission.
Numerous clinical studies demonstrate that subanaesthetic doses of dissociative anaesthetics, which are non-competitive antagonists at the NMDA receptor, replicate in normal subjects the cognitive impairments, negative symptoms and brain functional abnormalities of schizophrenia. Post-mortem and genetic studies have identified several abnormalities associated with schizophrenia that would interfere with the activation of the glycine modulatory site on the NMDA receptor. Placebo controlled clinical trials with agents that directly or indirectly activate the glycine modulatory site consistently reduce negative symptoms and frequently improve cognition in patients with chronic schizophrenia, who are receiving concurrent typical antipsychotics. Thus, there is convincing evidence that the glycine modulatory site on the NMDA receptor is a valid therapeutic target for improving cognition and associated negative symptoms in schizophrenia.
This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications.
Schizophrenia is a chronic, disabling psychiatric disorder that genetic studies have shown to be highly heritable. Although the dopamine hypothesis has dominated the thinking about the cause of schizophrenia for 40 years, post-mortem and genetic studies have provided little support for it. Rather, post-mortem studies point to hypofunction of subsets of GABAergic interneurons in the prefrontal cortex and the hippocampus. Furthermore, clinical pharmacologic, post-mortem and genetic studies have provided compelling evidence of hypofunction of a subpopulation of NMDA receptors in schizophrenia. In support of this inference, agents that directly or indirectly activate the glycine modulatory site on the NMDA receptor (the Glycine B receptor) reduce symptoms in chronic schizophrenia, especially negative symptoms and cognitive impairments. Electrophysiologic and pharmacologic studies suggest that the vulnerable NMDA receptors in schizophrenia may be concentrated on cortico-limbic GABAergic interneurons, thereby linking these two neuropathologic features of the disorder.
Cognitive impairment has emerged as an important new target in schizophrenia therapeutics in light of evidence that cognitive deficits are critically related to the functional of disability that is characteristic of the illness. Evidence is briefly reviewed supporting the idea that the cognitive impairment in schizophrenia is an attractive target for therapeutic intervention including: (1) there is a characteristic pattern of cognitive deficits that occur with very high frequency; (2) the deficits are relatively stable over time; and (3) cognitive deficits are relatively independent of the symptomatic manifestations of the illness. Thus, cognitive impairment appears to be a well-defined, reliable and distinct dimension of the illness.
Metabotropic glutamate 5 (mGlu5) receptors have been recently implicated in prefrontal cortex (PFC)-dependent executive functions
because inhibition of mGlu5 receptors impairs working memory and worsens cognitive-impairing effects of NMDA receptor antagonists.
To better understand the mechanisms by which mGlu5 receptors influence PFC function, we examined the effects of selective
mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), given alone or in combination with the NMDA receptor
antagonist MK801, on ensemble single unit activity in the medial PFC (mPFC) of behaving rats. MPEP decreased the spontaneous
burst activity of the majority of mPFC neurons. This inhibition was selective for the most active cells because greater decreases
were observed in neurons with higher baseline firing rates. MPEP augmented the effects of MK801 on burst activity, variability
of spike firing and random spike activity. These findings demonstrate that in awake animals mGlu5 receptors regulate the function
of PFC neurons by two related mechanisms: (i) rate-dependent excitatory influence on spontaneous burst activity; and (ii)
potentiation of NMDA receptor mediated effects on firing rate and burst activity. These mechanisms support the idea that modulation
of mGlu5 receptors may provide a pharmacological strategy for fine-tuning the temporal pattern of firing of PFC neurons.
We used in situ hybridization histochemistry to assess expression of dopamine receptors (D1R, D2R and D3R), neurotensin, proenkephalin and glutamate decarboxylase-67 (GAD67) in the prefrontal cortex, striatum, and/or nucleus accumbens in adult rats with neonatal ventral hippocampal (VH) lesions and in control animals after acute and chronic treatment with antipsychotic drugs clozapine and haloperidol. We also acquired these measures in a separate cohort of treatment-naïve sham and neonatally VH-lesioned rats used as an animal model of schizophrenia. Our results indicate that the neonatal VH lesion did not alter expression of D1R, D3R, neurotensin or proenkephalin expression in any brain region examined. However, D2R mRNA expression was down-regulated in the striatum, GAD67 mRNA was down-regulated in the prefrontal cortex and prodynorphin mRNA was up-regulated in the striatum of the VH-lesioned rats as compared with sham controls. Antipsychotic drugs did not alter expression of D1R, D2R or D3R receptor mRNAs but elevated neurotensin and proenkephalin expression in both groups of rats; patterns of changes were dependent on the duration of treatment and brain area examined. GAD67 mRNA was up-regulated by chronic antispychotics in the nucleus accumbens and the striatum and by chronic haloperidol in the prefrontal cortex in both sham and lesioned rats. These results indicate that the developmental VH lesion changed the striatal expression of D2R and prodynorphin and robustly compromised prefrontal GAD67 expression but did not modify drug-induced expression of any genes examined in this study.