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Decreased Dendritic Spine Density on Prefrontal Cortical Pyramidal Neurons in Schizophrenia
Abstract
The pathophysiological characteristics of schizophrenia appear to involve altered synaptic connectivity in the dorsolateral prefrontal cortex. Given the central role that layer 3 pyramidal neurons play in corticocortical and thalamocortical connectivity, we hypothesized that the excitatory inputs to these neurons are altered in subjects with schizophrenia.
To test this hypothesis, we determined the density of dendritic spines, markers of excitatory inputs, on the basilar dendrites of Golgi-impregnated pyramidal neurons in the superficial and deep portions of layer 3 in the dorsolateral prefrontal cortex (area 46) and in layer 3 of the primary visual cortex (area 17) of 15 schizophrenic subjects, 15 normal control subjects, and 15 nonschizophrenic subjects with a psychiatric illness (referred to as psychiatric subjects).
There was a significant effect of diagnosis on spine density only for deep layer 3 pyramidal neurons in area 46 (P = .006). In the schizophrenic subjects, spine density on these neurons was decreased by 23% and 16% compared with the normal control (P = .004) and psychiatric (P = .08) subjects, respectively. In contrast, spine density on neurons in superficial layer 3 in area 46 (P = .09) or in area 17 (P = .08) did not significantly differ across the 3 subject groups. Furthermore, spine density on deep layer 3 neurons in area 46 did not significantly (P = .81) differ between psychiatric subjects treated with antipsychotic agents and normal controls.
This region- and disease-specific decrease in dendritic spine density on dorsolateral prefrontal cortex layer 3 pyramidal cells is consistent with the hypothesis that the number of cortical and/or thalamic excitatory inputs to these neurons is altered in subjects with schizophrenia.
... In postmortem studies of schizophrenia, DLPFC L3PNs have been reported to have morphological alterations, such as smaller somal sizes (Pierri et al., 2001;Rajkowska et al., 1998;Pierri et al., 2003;Glantz and Lewis, 2000) and fewer dendritic spines (Glantz and Lewis, 2000;Garey et al., 1998;Konopaske et al., 2014), as well as molecular alterations, such as lower transcript levels of markers of energy production (e.g., cytochrome C oxidase subunit 4I1 (COX4I1) mRNA Arion et al., 2017), a central element in mitochondrial-mediated ATP synthesis (Čunátová et al., 2021)). Because somal size and spine number are highly correlated (Glantz and Lewis, 2000), and because spines are the site of most excitatory inputs to PNs, the postmortem findings in schizophrenia have contributed to the hypothesis that the morphological alterations in L3PNs result in lower excitatory drive to and less activity of L3PNs, with a consequent reduced drive for energy production (Glausier et al., 2020;Schoonover et al., 2020). ...
... In postmortem studies of schizophrenia, DLPFC L3PNs have been reported to have morphological alterations, such as smaller somal sizes (Pierri et al., 2001;Rajkowska et al., 1998;Pierri et al., 2003;Glantz and Lewis, 2000) and fewer dendritic spines (Glantz and Lewis, 2000;Garey et al., 1998;Konopaske et al., 2014), as well as molecular alterations, such as lower transcript levels of markers of energy production (e.g., cytochrome C oxidase subunit 4I1 (COX4I1) mRNA Arion et al., 2017), a central element in mitochondrial-mediated ATP synthesis (Čunátová et al., 2021)). Because somal size and spine number are highly correlated (Glantz and Lewis, 2000), and because spines are the site of most excitatory inputs to PNs, the postmortem findings in schizophrenia have contributed to the hypothesis that the morphological alterations in L3PNs result in lower excitatory drive to and less activity of L3PNs, with a consequent reduced drive for energy production (Glausier et al., 2020;Schoonover et al., 2020). ...
... In postmortem studies of schizophrenia, DLPFC L3PNs have been reported to have morphological alterations, such as smaller somal sizes (Pierri et al., 2001;Rajkowska et al., 1998;Pierri et al., 2003;Glantz and Lewis, 2000) and fewer dendritic spines (Glantz and Lewis, 2000;Garey et al., 1998;Konopaske et al., 2014), as well as molecular alterations, such as lower transcript levels of markers of energy production (e.g., cytochrome C oxidase subunit 4I1 (COX4I1) mRNA Arion et al., 2017), a central element in mitochondrial-mediated ATP synthesis (Čunátová et al., 2021)). Because somal size and spine number are highly correlated (Glantz and Lewis, 2000), and because spines are the site of most excitatory inputs to PNs, the postmortem findings in schizophrenia have contributed to the hypothesis that the morphological alterations in L3PNs result in lower excitatory drive to and less activity of L3PNs, with a consequent reduced drive for energy production (Glausier et al., 2020;Schoonover et al., 2020). ...
Background
Dorsolateral prefrontal cortex (DLPFC) dysfunction in schizophrenia appears to reflect alterations in layer 3 pyramidal neurons (L3PNs), including smaller cell bodies and lower expression of mitochondrial energy production genes. However, prior somal size studies used biased strategies for identifying L3PNs, and somal size and levels of energy production markers have not been assessed in individual L3PNs.
Study design
We combined fluorescent in situ hybridization (FISH) of vesicular glutamate transporter 1 (VGLUT1) mRNA and immunohistochemical-labeling of NeuN to determine if the cytoplasmic distribution of VGLUT1 mRNA permits the unbiased identification and somal size quantification of L3PNs. Dual-label FISH for VGLUT1 mRNA and cytochrome C oxidase subunit 4I1 (COX4I1) mRNA, a marker of energy production, was used to assess somal size and COX4I1 transcript levels in individual DLPFC L3PNs from schizophrenia (12 males; 2 females) and unaffected comparison (13 males; 1 female) subjects.
Study results
Measures of L3PN somal size with NeuN immunohistochemistry or VGLUT1 mRNA provided nearly identical results (ICC = 0.96, p < 0.0001). Mean somal size of VGLUT1-identified L3PNs was 8.7% smaller (p = 0.004) and mean COX4I1 mRNA levels per L3PN were 16.7% lower (p = 0.01) in schizophrenia. These measures were correlated across individual L3PNs in both subject groups (rrm = 0.81–0.86).
Conclusions
This preliminary study presents a novel method for combining unbiased neuronal identification with quantitative assessments of somal size and mRNA levels. We replicated findings of smaller somal size and lower COX4I1 mRNA levels in DLPFC L3PNs in schizophrenia. The normal scaling of COX4I1 mRNA levels with somal size in schizophrenia suggests that lower markers of energy production are secondary to L3PN morphological alterations in the illness.
... In schizophrenia, layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC) have a lower density of dendritic spines (Garey et al., 1998;Glantz and Lewis, 2000), the main sites of excitatory synaptic inputs onto PNs. These neurons also express lower levels of activity-dependent genes (Weickert et al., 2003;Hashimoto et al., 2005) and of genes involved in mitochondrial energy production (Arion et al., 2015;Arion et al., 2017;Glausier et al., 2020). ...
... Data from previous studies suggest that, in schizophrenia, PNs from DLPFC have reduced activity. For instance, these neurons have a lower density of dendritic spines (Garey et al., 1998;Glantz and Lewis, 2000), the main site of excitatory drive onto PNs, and also reduced expression of activity-dependent genes (Weickert et al., 2003;Hashimoto et al., 2005) and of genes involved in energy production (Arion et al., 2015;Arion et al., 2017;Glausier et al., 2020). ...
In schizophrenia, layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC) are thought to receive fewer excitatory synaptic inputs and to have lower expression levels of activity-dependent genes and of genes involved in mitochondrial energy production. In concert, these findings from previous studies suggest that DLPFC L3PNs are hypoactive in schizophrenia, disrupting the patterns of activity that are crucial for working memory, which is impaired in the illness. However, whether lower PN activity produces alterations in inhibitory and/or excitatory synaptic strength has not been tested in the primate DLPFC. Here, we decreased PN excitability in rhesus monkey DLPFC in vivo using adeno-associated viral vectors (AAVs) to produce Cre recombinase-mediated overexpression of Kir2.1 channels, a genetic silencing tool that efficiently decreases neuronal excitability. In acute slices prepared from DLPFC 7-12 weeks post-AAV microinjections, Kir2.1-overexpressing PNs had a significantly reduced excitability largely attributable to highly specific effects of the AAV-encoded Kir2.1 channels. Moreover, recordings of synaptic currents showed that Kir2.1-overexpressing DLPFC PNs had reduced strength of excitatory synapses whereas inhibitory synaptic inputs were not affected. The decrease in excitatory synaptic strength was not associated with changes in dendritic spine number, suggesting that excitatory synapse quantity was unaltered in Kir2.1-overexpressing DLPFC PNs. These findings suggest that, in schizophrenia, the excitatory synapses on hypoactive L3PNs are weaker and thus might represent a substrate for novel therapeutic interventions.
Significance Statement
In schizophrenia, dorsolateral prefrontal cortex (DLPFC) pyramidal neurons (PNs) have both transcriptional and structural alterations that suggest they are hypoactive. PN hypoactivity is thought to produce synaptic alterations in schizophrenia, however the effects of lower neuronal activity on synaptic function in primate DLPFC have not been examined. Here, we used, for the first time in primate neocortex, adeno-associated viral vectors (AAVs) to reduce PN excitability with Kir2.1 channel overexpression and tested if this manipulation altered the strength of synaptic inputs onto the Kir2.1-overexpressing PNs. Recordings in DLPFC slices showed that Kir2.1 overexpression depressed excitatory (but not inhibitory), synaptic currents, suggesting that, in schizophrenia, the hypoactivity of PNs might be exacerbated by reduced strength of the excitatory synapses they receive.
... Например, ген Disrupted-in-Schizophrenia 1 (DISC1) был впервые обнаружен в шотландской семье с SCZ [73], а затем во многих других популяциях [74]. Интересно, что нарушение белка DISC1 у мышей привело к нарушению регуляции иммунной сети генов, которые также нарушены при SCZ [75], что позволяет предположить, что неиммунные гены также могут модулировать областях мозга, таких как изменение объема гиппокампа и толщина коры, а также изменения плотности синапсов и белков [80,82], которые также наблюдаются при SCZ [86][87][88]. Изменения в амигдалакортикальных цепях были связаны с SCZ [89], и еще одно исследование показало, что MIA усиливает глутаматергическую нейротрансмиссию между этими цепями за счет увеличения синаптической силы у подвергшихся воздействию потомков [90]. Исследования в этой области показали, что индуцированный MIA дефицит развития нервной системы зависит от воспалительной передачи сигналов через материнский микробиом [91]. ...
... При SCZ наблюдается аномальная активность во многих нейронных сетях и областях мозга [149]. Имеются веские доказательства того, что возбуждающие нейронные MEDLINE.RU, ТОМ 25, ПСИХИАТРИЯ, 10 АПРЕЛЯ 2024 271 цепи изменяются при SCZ [86,149,150]. Блокада рецепторов N-метил-D-аспартата (NMDAR) у здоровых людей приводит к психотическим симптомам и когнитивным нарушениям, которые напоминают наблюдаемые при SCZ [151]. Кроме того, уровни как мРНК, так и белков-субъединиц NMDA NR1 и NR2C снижены в посмертной ткани головного мозга при SCZ [152]. ...
Schizophrenia is a disorder with a heterogeneous etiology, involving a complex interaction between genetic and environmental risk factors. The immune system is now known to play a vital role in the function and pathology of the nervous system by regulating neuronal and glial development, synaptic plasticity, and behavior. In this regard, the immune system is positioned as a common link between the seemingly diverse genetic and environmental risk factors for schizophrenia. Synthesizing information about how the brain's interactions with the immune system are influenced by multiple factors and how these factors may interact in schizophrenia is necessary to better understand the pathogenesis of this disease.
This article provides an overview of the genetic risk factors for schizophrenia that modulate immune function and how the consequences of these risk factors relate to microglial function and dysfunction. It is hypothesized that the morphological and signaling deficits of the blood-brain barrier observed in some people with schizophrenia may act as a gateway between peripheral and central nervous system inflammation, thereby affecting essential microglial functions. In addition, the various roles that microglia play in response to neuroinflammation and their impact on brain development and homeostasis, as well as the pathophysiology of schizophrenia, are reviewed.
... E/I imbalance has been suggested to involve aberrant neural connectivity linked to a reduction of brain volume in the frontal cortex and HC linked with a loss of synapses rather than neurons themselves. 96,97 Indeed, psychiatric disorders have been associated with reduced dendritic outgrowths of PV-INs and with more immature dendritic spines on pyramidal cells in postmortem studies 96,97 and in mouse models. 98 In line with this, Bdnf Pax2 KO mice exhibit normal numbers of PV-INs and normal BDNF mRNA/protein levels in the AC and HC, but immature (low) levels of PV in dendrites that persist also into adulthood ( Figure S4). ...
... E/I imbalance has been suggested to involve aberrant neural connectivity linked to a reduction of brain volume in the frontal cortex and HC linked with a loss of synapses rather than neurons themselves. 96,97 Indeed, psychiatric disorders have been associated with reduced dendritic outgrowths of PV-INs and with more immature dendritic spines on pyramidal cells in postmortem studies 96,97 and in mouse models. 98 In line with this, Bdnf Pax2 KO mice exhibit normal numbers of PV-INs and normal BDNF mRNA/protein levels in the AC and HC, but immature (low) levels of PV in dendrites that persist also into adulthood ( Figure S4). ...
Autism spectrum disorder is discussed in the context of altered neural oscillations and imbalanced cortical excitation–inhibition of cortical origin. We studied here whether developmental changes in peripheral auditory processing, while preserving basic hearing function, lead to altered cortical oscillations. Local field potentials (LFPs) were recorded from auditory, visual, and prefrontal cortices and the hippocampus of BdnfPax2 KO mice. These mice develop an autism‐like behavioral phenotype through deletion of BDNF in Pax2+ interneuron precursors, affecting lower brainstem functions, but not frontal brain regions directly. Evoked LFP responses to behaviorally relevant auditory stimuli were weaker in the auditory cortex of BdnfPax2 KOs, connected to maturation deficits of high‐spontaneous rate auditory nerve fibers. This was correlated with enhanced spontaneous and induced LFP power, excitation–inhibition imbalance, and dendritic spine immaturity, mirroring autistic phenotypes. Thus, impairments in peripheral high‐spontaneous rate fibers alter spike synchrony and subsequently cortical processing relevant for normal communication and behavior.
... Among the neurons that constitute the networks, there is one type called "delay cells," which can save the working memory information for subsequent calling and responding. For example, in a visuospatial delay reactive task, delay cells fire continuously in the delay stage and could project to aimed areas even without visual stimulus (Glantz and Lewis, 2000); thus, we could see their importance in cognitive modulation. From the above, it is informed that dynamic network connection is the basis of cognitive ability. ...
... Through electrophysiological and anatomical research on tasks of spatial working memory, we know that the parietal association cortex projects sensory inputs to the PFC, and the repeated excitation of glutamate pyramidal neurons microcircuits could result in the persistent firing of delay cells (Kritzer and Goldman-Rakic, 1995). A further study showed that adjacent neurons with similar functions could keep persistent firing by reciprocal stimulation through connections between their dendritic spines, thus independent of the repeated stimulation of visual sense (Glantz and Lewis, 2000). This obviously strengthens the maintenance of memory. ...
Parkinson's disease can affect not only motor functions but also cognitive abilities, leading to cognitive impairment. One common issue in Parkinson's disease with cognitive dysfunction is the difficulty in executive functioning. Executive functions help us plan, organize, and control our actions based on our goals. The brain area responsible for executive functions is called the prefrontal cortex. It acts as the command center for the brain, especially when it comes to regulating executive functions. The role of the prefrontal cortex in cognitive processes is influenced by a chemical messenger called dopamine. However, little is known about how dopamine affects the cognitive functions of patients with Parkinson's disease. In this article, the authors review the latest research on this topic. They start by looking at how the dopaminergic system, is altered in Parkinson's disease with executive dysfunction. Then, they explore how these changes in dopamine impact the synaptic structure, electrical activity, and connection components of the prefrontal cortex. The authors also summarize the relationship between Parkinson's disease and dopamine-related cognitive issues. This information may offer valuable insights and directions for further research and improvement in the clinical treatment of cognitive impairment in Parkinson's disease.
... There is growing evidence to suggest that the balance between excitatory and inhibitory network in the mPFC is crucial for the regulation of working memory in normal mice [34,35,41,42]. Decreased dendritic spine density in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia has been replicated in numerous studies [43][44][45] and proposed to play a key pathophysiological role in schizophrenia [46]. The dendritic spine analysis presented here clearly indicated that chronic PCP administration leads to dendritic spine loss in layer 2-3 of the PL. ...
... Previous studies have revealed that the size of dendritic spine head is closely linked to synaptic function such as the size of postsynaptic density, the number of AMPA receptors, and synaptic strength [47][48][49]. These anatomical changes observed in the present study suggest that our PCP model exhibits attenuated excitatory inputs from other cortex in the PL, which is consistent with the morphological features observed in patients with schizophrenia, such as reductions in dendritic spines [43][44][45]50] and VGLUT1 [51,52] in layer 3 of the DLPFC. ...
One of the critical unmet medical needs in schizophrenia is the treatment for cognitive deficits. However, the neural circuit mechanisms of them remain unresolved. Previous studies utilizing animal models of schizophrenia did not consider the fact that patients with schizophrenia generally cannot discontinue antipsychotic medication due to the high risk of relapse. Here, we used multi-dimensional approaches, including histological analysis of the prelimbic cortex (PL), LC-MS/MS-based in vivo dopamine D2 receptor occupancy analysis for antipsychotics, in vivo calcium imaging, and behavioral analyses of mice using chemogenetics to investigate neural mechanisms and potential therapeutic strategies for working memory deficit in a chronic phencyclidine (PCP) mouse model of schizophrenia. Chronic PCP administration led to alterations in excitatory and inhibitory synapses, specifically in dendritic spines of pyramidal neurons, vesicular glutamate transporter 1 (VGLUT1) positive terminals, and parvalbumin (PV) positive GABAergic interneurons located in layer 2–3 of the PL. Continuous administration of olanzapine, which achieved a sustained therapeutic window of dopamine D2 receptor occupancy (60–80%) in the striatum, did not ameliorate these synaptic abnormalities and working memory deficit in the chronic PCP-treated mice. We demonstrated that chemogenetic activation of PV neurons in the PL, as confirmed by in vivo calcium imaging, ameliorated working memory deficit in this model even under clinically comparable olanzapine treatment which by itself inhibited only PCP-induced psychomotor hyperactivity. Our study suggests that targeting prefrontal PV neurons could be a promising therapeutic intervention for cognitive deficits in schizophrenia in combination with antipsychotic medication.
... The decreased recurrent activity due to spine loss that we found could play a role in the reduced sustained neural activity in depression patients when processing positive emotional stimuli 39 . Our results may extend to diseases such as Alzheimer's disease 40 and schizophrenia 41 , where spine loss and reduced cortical activity during response 42 are also observed and are correlated with cognitive deficits 43 . We modeled spine loss according to rodent data in mild chronic stress, which is of a similar order of magnitude to the level of spine synapse loss in post-mortem human tissues 6,7 although somewhat lower. ...
Major depressive disorder (depression) is associated with altered dendritic structure and function in excitatory cortical pyramidal neurons, due to decreased inhibition from somatostatin interneurons and loss of spines and associated synapses, as indicated in postmortem human studies. Dendrites play an important role in signal processing as they receive the majority of synaptic inputs and exhibit nonlinear properties including backpropagating action potentials and dendritic Na+ spikes that enhance the computational power of the neuron. However, it is currently unclear how depression-related dendritic changes impact the integration of signals. Here, we expanded our previous data-driven detailed computational models of human cortical microcircuits in health and depression to include active dendritic properties that enable backpropagating action potentials as measured in human neurons, and spine loss in depression in terms of synapse loss and altered intrinsic property. We show that spine loss dampens signal response and thus results in a larger impairment of cortical function such as signal detection than due to reduced somatostatin interneuron inhibition alone. We further show that the altered intrinsic properties due to spine loss abolish nonlinear dendritic integration of signals and impair recurrent microcircuit activity. Our study thus mechanistically links cellular changes in depression to impaired dendritic processing in human cortical microcircuits.
... Given the D1R-mediated increase in the excitability of fast-spiking, putative PV Main 4 neurons, which participate in shaping working memory processes during distractor challenges in vivo, we hypothesize that higher D1R expression levels in layer III dlPFC PV neurons in marmosets, compared to macaques, may significantly degrade working memory performance and specifically distractor resistance. Because these layer III microcircuits could be altered in schizophrenia 34 , stage III/IV Alzheimer's disease 35 , and stress and mood disorders 36 , understanding their common and divergent properties across primates is critical when modeling neural mechanisms of cognitive disorders. ...
Marmosets and macaques are common non-human primate models of cognition, but evidence suggests that marmosets perform more poorly and appear more distractible during cognitive tasks. Prior experimental and theoretical work in macaques suggests that dopaminergic modulation and inhibitory parvalbumin (PV) neurons could contribute to distractibility during cognitive performance. Thus, we compared the two species using a visual fixation task with distractors, performed molecular and anatomical analyses in the dorsolateral prefrontal cortex (dlPFC), and linked functional microcircuitry with cognitive performance using computational modeling. We found that marmosets are indeed more distractible than macaques, and that marmoset dlPFC PV neurons contain higher levels of dopamine-1 receptor (D1R) transcripts and protein. The computational model suggested that higher D1R expression in marmoset dlPFC PV neurons may induce distractibility within the typical, mid D1R stimulation range. Our interdisciplinary study can inform species choice for translational studies of cognition, and clarify microcircuit mechanisms for distractor resistance.
... The underlying cause of these macrostructural changes occurring around the onset of psychosis remains unclear, but they are thought to reflect accumulated alterations at the cellular level. Postmortem studies, for instance, have reported reduced somal sizes of pyramidal neurons [24][25][26][27][28], lower spine density, and less dendritic arborization [29][30][31] in schizophrenia, all of which could account for GM volume reductions [32][33][34]. It is hypothesized that such microstructural cellular changes might accumulate before the manifestation of detectable MR macrostructural changes, potentially serving as an earlier sign of an unfavorable clinical trajectory. ...
Recent studies show that accelerated cortical gray matter (GM) volume reduction seen in anatomical MRI can help distinguish between individuals at clinical high risk (CHR) for psychosis who will develop psychosis and those who will not. This reduction is suggested to represent atypical developmental or degenerative changes accompanying an accumulation of microstructural changes, such as decreased spine density and dendritic arborization. Detecting the microstructural sources of these changes before they accumulate into volume loss is crucial. Our study aimed to detect these microstructural GM alterations using diffusion MRI (dMRI). We tested for baseline and longitudinal group differences in anatomical and dMRI data from 160 individuals at CHR and 96 healthy controls (HC) acquired in a single imaging site. Of the CHR individuals, 33 developed psychosis (CHR-P), while 127 did not (CHR-NP). Among all participants, longitudinal data was available for 45 HCs, 17 CHR-P, and 66 CHR-NP. Eight cortical lobes were examined for GM volume and GM microstructure. A novel dMRI measure, interstitial free water (iFW), was used to quantify GM microstructure by eliminating cerebrospinal fluid contribution. Additionally, we assessed whether these measures differentiated the CHR-P from the CHR-NP. In addition, for completeness, we also investigated changes in cortical thickness and in white matter (WM) microstructure. At baseline the CHR group had significantly higher iFW than HC in the prefrontal, temporal, parietal, and occipital lobes, while volume was reduced only in the temporal lobe. Neither iFW nor volume differentiated between the CHR-P and CHR-NP groups at baseline. However, in many brain areas, the CHR-P group demonstrated significantly accelerated changes (iFW increase and volume reduction) with time than the CHR-NP group. Cortical thickness provided similar results as volume, and there were no significant changes in WM microstructure. Our results demonstrate that microstructural GM changes in individuals at CHR have a wider extent than volumetric changes or microstructural WM changes, and they predate the acceleration of brain changes that occur around psychosis onset. Microstructural GM changes, as reflected by the increased iFW, are thus an early pathology at the prodromal stage of psychosis that may be useful for a better mechanistic understanding of psychosis development.
... With respect to schizophrenia, the very earliest stem cell reports (6,7) indeed reproduced the most basic cellular phenotypes long reported in postmortem analyses: reduced neurite outgrowth (8) and synaptic density (9). Subsequent stem cell findings, across idiopathic (10), syndromic rare deletions of 22q11.2 ...
... As introduced earlier, the E/I imbalance causing impaired γ rhythm stems from glutamate and GABA coexistent dysfunction and has been robustly reported in psychiatric and neurological disorders [32,34,339]. Altered levels of Glx, reduced pyramidal cell density, and attenuated NMDAR neurotransmission characterize ScZ, with differences depending on disease stage and treatment history [340,341]. Importantly, a reduction and/or hypo-activity of NMDAR has been documented and linked to GABAergic circuits dysfunction [342]. Indeed, NMDAR impairments generate abnormalities in levels of GAD67 in PV+ interneurons, as well as in PV expression [140,196], supporting the role of NMDAR-mediated glutamatergic signaling in GABAergic interneuronal development and behavior [343]. ...
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.
... Structural and functional modifications of dendritic spines are central to brain development and plasticity (Spruston, 2008). Studies from postmortem brains of subjects with neurodevelopmental disorders including schizophrenia demonstrate altered density and morphology of dendritic spines, particularly in the frontal cortex (Glantz and Lewis, 2000;Black et al., 2004). IQGAP scaffold proteins facilitate the formation of complexes that regulate cytoskeletal dynamics including microtubules (Cao et al., 2015b). ...
Genome-wide association studies have revealed >270 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, few studies so far have profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects, or the effect of antipsychotic treatment on such epigenetic marks. Here, we conducted ChIP-seq analyses focusing on histone marks indicative of active enhancers (H3K27ac) and active promoters (H3K4me3), alongside RNA-seq, using frontal cortex samples from antipsychotic-free (AF) and antipsychotic-treated (AT) individuals with schizophrenia, as well as individually matched controls (n=58). Schizophrenia subjects exhibited thousands of neuronal and non-neuronal epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1 , DISC1, and DRD3 . By analyzing the AF and AT cohorts separately, we identified schizophrenia-associated alterations in specific transcription factors, their regulatees, and epigenomic and transcriptomic features that were reversed by antipsychotic treatment; as well as those that represented a consequence of antipsychotic medication rather than a hallmark of schizophrenia in postmortem human brain samples. Notably, we also found that the effect of age on epigenomic landscapes was more pronounced in frontal cortex of AT-schizophrenics, as compared to AF-schizophrenics and controls. Together, these data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark for the first time on the impact of age and antipsychotic treatment on chromatin organization.
... Prefrontal intrinsic connectivity is correlated with negative symptom (Hoptman et al., 2002;Wolkin et al., 2003) and decreased frontal-temporal connectivity is correlated with impairments in executive functions and memory (Kubicki et al., 2002(Kubicki et al., , 2003. At a cellular level, postmortem studies revealed cytoarchitectonic alterations in the PFC of SZ, such as fewer dendritic spines in PN (Garey et al., 1998;Glantz and Lewis, 2000) reduction of neuropil (Selemon et al., 2004) and reduction of the mean clustering distance between cells (Casanova et al., 2008). Given its functional relevance, one of the most important post-mortem findings has been the reduction of the density of IN (Benes and Berretta, 2001) and GAD67 expressing cells in the PFC of SZ patients (Guidotti et al., 2000;Volk et al., 2000). ...
Cognitive control of behavior is crucial for well-being, as allows subject to adapt to changing environments in a goal-directed way. Changes in cognitive control of behavior is observed during cognitive decline in elderly and in pathological mental conditions. Therefore, the recovery of cognitive control may provide a reliable preventive and therapeutic strategy. However, its neural basis is not completely understood. Cognitive control is supported by the prefrontal cortex, structure that integrates relevant information for the appropriate organization of behavior. At neurophysiological level, it is suggested that cognitive control is supported by local and large-scale synchronization of oscillatory activity patterns and neural spiking activity between the prefrontal cortex and distributed neural networks. In this review, we focus mainly on rodent models approaching the neuronal origin of these prefrontal patterns, and the cognitive and behavioral relevance of its coordination with distributed brain systems. We also examine the relationship between cognitive control and neural activity patterns in the prefrontal cortex, and its role in normal cognitive decline and pathological mental conditions. Finally, based on these body of evidence, we propose a common mechanism that may underlie the impaired cognitive control of behavior.
... Such synaptic alterations, particularly within the intricate web of glutamatergic pathways, are posited to be instrumental in precipitating the onset of schizophrenia. This hypothesis gained support from post-mortem studies conducted on individuals with schizophrenia, revealing noteworthy reductions in dendritic density within cortical brain regions-an observation that aligns with the concept of aberrant synaptic dynamics as a precursor to the disorder [12]. ...
Background and Objectives: Neuroimaging reveals a link between psychiatric conditions and brain structural–functional changes, prompting a paradigm shift in viewing schizophrenia as a neurodevelopmental disorder. This study aims to identify and compare structural brain changes found during the first schizophrenia episode with those found after more than 5 years of illness. Materials and Methods: This prospective study involved 149 participants enrolled between 1 January 2019 and 31 December 2021. The participants were categorized into three groups: the first comprises 51 individuals with an initial psychotic episode, the second consists of 49 patients diagnosed with schizophrenia for over 5 years, and a control group comprising 50 individuals without a diagnosis of schizophrenia or any other psychotic disorder. All participants underwent brain CT examinations. Results: The study examined all three groups: first-episode schizophrenia (FES), schizophrenia (SCZ), and the control group. The FES group had a mean age of 26.35 years and a mean duration of illness of 1.2 years. The SCZ group, with a mean age of 40.08 years, had been diagnosed with schizophrenia for an average of 15.12 years. The control group, with a mean age of 34.60 years, had no schizophrenia diagnosis. Structural measurements revealed widening of frontal horns and lateral ventricles in the SCZ group compared to FES and the FES group compared to the control group. Differences in the dimensions of the third ventricle were noted between SCZ and FES, while no distinction was observed between FES and the control group. The fourth ventricle had similar measurements in FES and SCZ groups, both exceeding those of the control group. Our results showed higher densities in the frontal lobe in schizophrenia patients compared to FES and the control group, with the control group consistently displaying the lowest densities. Conclusions: In summary, our comparative imaging analysis of schizophrenia patients, first-episode schizophrenia, and control patients revealed distinct ventricular patterns, with SCZ showing greater widening than FES and FES wider than the control group. Frontal lobe density, assessed via cerebral CT scans, indicated a higher density in the SCZ group in both anterior and posterior cortex portions compared to FES and the control group, while the left posterior cortex in FES had the highest density. These findings highlight unique neuroanatomical features across groups, shedding light on structural differences associated with different stages of schizophrenia.
... Given the major role of stress in exacerbating the symptoms of cognitive disorders, the current data also have relevance to the potential treatment of PFC deficits in mental illness. For example, deficits in dlPFC function are evident in schizophrenia (Weinberger et al., 1986;Glantz and Lewis, 2000;Perlstein et al., 2001;Driesen et al., 2008;Barch and Ceaser, 2012), depression (Holmes et al., 2019), bipolar disorder (Blumberg et al., 1999(Blumberg et al., , 2003, PTSD (Harnett et al., 2021;Aupperle et al., 2012;Holmes et al., 2018), substance abuse (Smith et al., 2023), and Alzheimer's disease (Hof and Morrison, 1991;Schroeter et al., 2012), all of which are worsened or caused by stress exposure (Mazure, 1995;Sinha, 2007;Hart et al., 2017;Georgiades et al., 2023;Johansson et al., 2013;Nook et al., 2018). Treatment strategies for many of these disorders utilize repetitive transcranial magnetic stimulation to strengthen the left dlPFC and help restore top-down regulation e.g (George et al., 2013;Gomis-Vicent et al., 2019), and thus, pharmacological strategies that restore PFC top-down regulation may also be helpful. ...
Uncontrollable stress exposure impairs working memory and reduces the firing of dorsolateral prefrontal cortex (dlPFC) “Delay cells”, involving high levels of norepinephrine and dopamine release. Previous work has focused on catecholamine actions on dlPFC pyramidal cells, but inhibitory interneurons may contribute as well. The current study combined immunohistochemistry and multi-scale microscopy with iontophoretic physiology and behavioral analyses to examine the effects of beta1-noradrenergic receptors (β1-ARs) on inhibitory neurons in layer III dlPFC. We found β1-AR robustly expressed on different classes of inhibitory neurons labeled by the calcium-binding proteins calbindin (CB), calretinin (CR), and parvalbumin (PV). Immunoelectron microscopy confirmed β1-AR expression on the plasma membrane of PV-expressing dendrites. PV interneurons can be identified as fast-spiking (FS) in physiological recordings, and thus were studied in macaques performing a working memory task. Iontophoresis of a β1-AR agonist had a mixed effect, increasing the firing of a subset and decreasing the firing of others, likely reflecting loss of firing of the entire microcircuit. This loss of overall firing likely contributes to impaired working memory during stress, as pretreatment with the selective β1-AR antagonist, nebivolol, prevented stress-induced working memory deficits. Thus, selective β1-AR antagonists may be helpful in treating stress-related disorders.
... However, unlike Kolluri et el., Glantz and Lewis have shown decreased dendritic spine density in prefrontal cortical neurons in schizophrenia. The authors demonstrated that the dendritic spineloss in the DLPFC is seen in pyramidal cells in deep layer III (Glantz and Lewis 2000). ...
Since Cajal introduced dendritic spines in the 19th century, they have attained considerable attention, especially in neuropsychiatric and neurologic disorders. Multiple roles of dendritic spine malfunction and pathology in the progression of various diseases have been reported. Thus, it is inevitable to consider these structures as new therapeutic targets for treating neuropsychiatric and neurologic disorders such as autism spectrum disorders, schizophrenia, dementia, Down syndrome, etc. Therefore, we attempted to prepare a narrative review of the literature regarding the role of dendritic spines in the pathogenesis of aforementioned diseases and to shed new light on their pathophysiology.
... Volumetric measures are crude measures influenced by many pathologies, making it difficult to interpret findings biologically. However, it is hypothesized that volume loss might reflect an accumulation of earlier microstructural changes [41][42][43] and that identifying these microstructural changes might allow earlier detection and treatment of, e.g., individuals at risk for cognitive impairments. ...
Increasing evidence points toward the role of the extracellular matrix, specifically matrix metalloproteinase 9 (MMP-9), in the pathophysiology of psychosis. MMP-9 is a critical regulator of the crosstalk between peripheral and central inflammation, extracellular matrix remodeling, hippocampal development, synaptic pruning, and neuroplasticity. Here, we aim to characterize the relationship between plasma MMP-9 activity, hippocampal microstructure, and cognition in healthy individuals and individuals with early phase psychosis. We collected clinical, blood, and structural and diffusion-weighted magnetic resonance imaging data from 39 individuals with early phase psychosis and 44 age and sex-matched healthy individuals. We measured MMP-9 plasma activity, hippocampal extracellular free water (FW) levels, and hippocampal volumes. We used regression analyses to compare MMP-9 activity, hippocampal FW, and volumes between groups. We then examined associations between MMP-9 activity, FW levels, hippocampal volumes, and cognitive performance assessed with the MATRICS battery. All analyses were controlled for age, sex, body mass index, cigarette smoking, and years of education. Individuals with early phase psychosis demonstrated higher MMP-9 activity ( p < 0.0002), higher left ( p < 0.05) and right ( p < 0.05) hippocampal FW levels, and lower left ( p < 0.05) and right ( p < 0.05) hippocampal volume than healthy individuals. MMP-9 activity correlated positively with hippocampal FW levels (all participants and individuals with early phase psychosis) and negatively with hippocampal volumes (all participants and healthy individuals). Higher MMP-9 activity and higher hippocampal FW levels were associated with slower processing speed and worse working memory performance in all participants. Our findings show an association between MMP-9 activity and hippocampal microstructural alterations in psychosis and an association between MMP-9 activity and cognitive performance. Further, more extensive longitudinal studies should examine the therapeutic potential of MMP-9 modulators in psychosis.
... Indeed, synaptic pruning is considered essential for optimizing activity propagation and memory capacity [54][55][56]. Additionally, it is commonly believed that synaptic pruning and rewiring dysfunction are among the neural correlates of developmental disorders such as autism or schizophrenia [57,58], leading to a higher or lower synaptic density with respect to neurotypical subjects, respectively [59][60][61]. ...
The brain is one of the most intricate systems and the quest for simulating the neuronal dynamics has led to the development of several approaches and simulation tools able to represent the behavior of portions of the brain with different levels of detail. Among the different techniques that we can adopt to shed light on neuronal dynamics, mean-field models and spiking neural networks are two of the most relevant, and are introduced in Part I of this doctoral thesis. In particular, spiking neural network models have become an effective tool to study brain functions as they capture several aspects of natural neural networks, with every neuron being characterized by a membrane potential and a mechanism to emit electrical pulses for communication with other neurons. While mean-field approaches are suitable for the simulations of models of the entire brain with population resolution, spiking neural networks are able to simulate portions of the brain at cellular level. However, recent computing technologies are paving the way for large-scale simulations through the usage of cutting-edge supercomputer clusters, and it is of fundamental importance for computational neuroscientists to have tools able to take advantage of these technologies. In recent years, Graphical Processing Units (GPUs) established themselves as promising hardware to be employed for such simulations, thanks to their high degree of parallelism, and several GPU-based simulation codes have been developed. In Part II of this thesis, we describe the GPU code for spiking neural network simulations NEST GPU, which is able to efficiently exploit GPU hardware spanning from consumer GPUs to data-center cards employed in MPI-GPU clusters. The thesis is devoted both to evaluate the performance of such a simulator in the simulation of neuroscientifically relevant models, and, most importantly, to validate the results of the neuronal dynamics with respect to established spiking network simulators such as NEST.
To better understand the link between brain functioning and high-level cognitive processes with low-level neuronal activity, there is the need to provide realistic models both for the neurons and the synapses. Indeed, there is broad consensus in the neuroscientific community that synaptic mechanisms, such as short-term synaptic plasticity and structural synaptic plasticity underlie cognitive processes like working memory and learning. Part III of this thesis is devoted to developing simulation and theoretical frameworks that shed light on the possible relation between these synaptic mechanisms and the previously mentioned cognitive processes. In particular, Chapter 7 focuses on the simulation of a working memory spiking network driven by short-term plasticity (STP), which is believed to be responsible for the activity-silent mechanisms that characterize working memory networks, while Chapter 8 presents a theoretical framework able to describe a learning process mediated by structural synaptic plasticity, evaluating the memory capacity of the network as a function of the simulation parameters.
This thesis aims to start facing the challenge of the study of high-level cognitive processes through simulations of large-scale neuronal networks. In a framework in which computing technologies are opening to the realm of large-scale simulations through the usage of GPU clusters, there is a need for simulators capable of exploiting this fast-growing hardware being efficient and, more importantly, reliable. Additionally, modeling neuron and synaptic scale mechanisms can shed light on their impact on high-level cognitive processes such as learning and memory and, together with large-scale simulations at neuron resolution, it would be possible to estimate the relation of these mechanisms and the dynamics of neuronal networks representing a significant portion of the brain. These works are oriented toward the development of more detailed network models, which will pave the way for the usage of these tools in medicine as support for novel therapies.
... At this point we can only speculate what neural substrate may underly reduced N100 amplitude and thus altered function of AC pyramidal cells in SCZ spect . Altered synaptic pruning 120,121 resulting in reduced dendritic spine density on cortical pyramidal neurons 122,123 , is part of the pathogenesis of SCZ spect . Reduced dendritic spine density on AC pyramidal cells (and interneurons) may result in desynchronized ring, a decreased summation of postsynaptic potentials and thus in reduced N100 amplitude in SCZ spect 116,124 . ...
Schizophrenia spectrum disorders (SCZ spect ) are associated with altered function in the auditory cortex (AC), indicated by reduced N100 amplitude of the auditory evoked potential (AEP). While the neural substrate behind reduced N100 amplitude remains elusive, myelination in the AC may play a role. We compared N100 amplitude and magnetic resonance imaging (MRI) T1 weighted and T2 weighted ratio (T1w/T2w-ratio) as a proxy of myelination, in the primary AC (AC1) and secondary AC (AC2) between SCZ spect (n = 33, 48% women) and healthy controls (HC, n = 144, 49% women). Further, we examined associations between N100 amplitude and T1w/T2w-ratios in SCZ spect and HC. We finally explored N100 amplitude and T1w/T2w-ratios in the AC1/AC2 and association between N100 amplitude and T1w/T2w-ratios between male and female SCZ spect and HC. N100 amplitude did not differ between SCZ spect and HC or between female SCZ spect and female HC, but was significantly reduced in male SCZ spect compared to male HC (est = 4.3, se = 1.63, t = 2.63, p = 0.010). Further, T1w/T2w ratios in the AC1/AC2 did not differ between any groups. Finally, N100 amplitude was not associated with T1/T2-ratios in the AC1/AC2 in any groups. Reduced N100 amplitude in male SCZ spect compared to male HC, suggest that sex-specific effects should be considered in research on SCZ spect neurophysiology. Our findings did not support the hypothesis that reduced myelination in the AC1/AC2, as indexed by T1w/T2w-ratio, underlies N100 abnormalities in SCZ spect . However, more precise estimates of intracortical myelin are needed to confirm this.
... Evidence demonstrated that the schizophrenia brain reduced dendritic spine density and altered synaptic plasticity [45,46]. Mounting evidence suggests that actin remodeling is critical to synaptogenesis, synaptic plasticity, and the development of neurites in developing neurons [47,48]. ...
The glutamate ionotropic kainate receptors, encoded by the GRIK gene family, are composed of four subunits and function as ligand-activated ion channels. They play a critical role in regulating synaptic transmission and various synaptic receptors’ processes, as well as in the pathophysiology of schizophrenia. However, their functions and mechanisms of action need to be better understood and are worthy of exploration. To further understand the exact role of the kainate receptors in vitro, we generated kainate-receptor-knockout (KO) isogenic SH-SY5Y cell lines using the CRISPR/Cas9-mediated gene editing method. We conducted RNA sequencing (RNA-seq) to determine the differentially expressed genes (DEGs) in the isogenic edited cells and used rhodamine-phalloidin staining to quantitate filamentous actin (F-actin) in differentiated edited cells. The RNA-seq and the Gene Ontology enrichment analysis revealed that the genetic deletion of the GRIK1, GRIK2, and GRIK4 genes disturbed multiple genes involved in numerous signal pathways, including a converging pathway related to the synaptic membrane. An enrichment analysis of gene–disease associations indicated that DEGs in the edited cell lines were associated with several neuropsychiatric disorders, especially schizophrenia. In the morphology study, fluorescent images show that less F-actin was expressed in differentiated SH-SY5Y cells with GRIK1, GRIK2, or GRIK4 deficiency than wild-type cells. Our data indicate that kainate receptor deficiency might disturb synaptic-membrane-associated genes, and elucidating these genes should shed some light on the pathophysiology of schizophrenia. Furthermore, the transcriptomic profiles for kainate receptor deficiency of SH-SY5Y cells contribute to emerging evidence for the novel mechanisms underlying the effect of kainate receptors and the pathophysiology of schizophrenia. In addition, our data suggest that kainate-receptor-mediated F-actin remodeling may be a candidate mechanism underlying schizophrenia.
... Similarly, electro-encephalographic (EEG) and MEG recordings from brains of schizophrenia patients showed decreased amplitude of gamma oscillations [12,13]; MRS studies have shown that GABA concentration in patients with schizophrenia was reduced, whereas glutamate increased [14][15][16]. At a cellular level, post-mortem studies in autistic subjects have identified increased spine densities in cortical pyramidal neurons [17] and a reduced parvalbumin-positive interneuron population in the pre-frontal cortex (PFC) [18], while patients with schizophrenia showed decreased expression of glutamate decarboxylase 67 (GAD67) in parvalbumin-positive interneurons [19][20][21]. Additionally, increased E/I ratio has been identified with MRS due to either increased glutamate or decreased GABA levels in a variety of psychiatric conditions associated with NDD, including epilepsy [22], anxiety [23,24], depression [25][26][27] and obsessive-compulsive disorder [28]. ...
Introduction: Sex differences exist in the prevalence of neurodevelopmental disorders (NDDs). Part of the aetiology of NDDs has been proposed to be alterations in the balance between excitatory and inhibitory neurotransmission, leading to the question of whether males and females respond differently to altered neurotransmitter balance. We investigated whether pharmacological alteration of GABAA signalling in early development results in sex-dependent changes in adult behaviours associated with NDDs. Methods: Male and female C57BL/6J mice received intraperitoneal injections of 0.5mg/kg muscimol or saline on postnatal days (P) 3-5 and were subjected to behavioural testing, specifically open field, light dark box, marble burying, sucralose preference, social interaction and olfactory habituation/dishabituation tests between P60-90. Results: Early postnatal administration of muscimol resulted in reduced anxiety in the light dark box test in both male and female adult mice. Muscimol reduced sucralose preference in males, but not females, whereas female mice showed reduced social behaviours. Regional alterations in cortical thickness were observed in the weeks following GABAA receptor activation, pointing to an evolving structural difference in the brain underlying adult behaviour. Conclusions: We conclude that activation of the GABAA receptor in the first week of life resulted in long-lasting changes in a range of behaviours in adulthood following altered neurodevelopment. Sex of the individual affected the nature and severity of these abnormalities, explaining part of the varied pathophysiology and neurodevelopmental diagnosis that derive from excitatory/inhibitory imbalance.
... The filled triangles represent the averaged performance of four aged monkeys on a spatial working memory task for individual test sessions across the baseline. (adapted from Castner and Goldman-Rakic, 2004 reduced neuron density finding (e.g., Glantz and Lewis, 2000) and have also shown that reduced neuronal density in schizophrenia may be a general effect across much of the cortex, which makes sense given the extensive prefrontal cortical connections not only across the cortex but also across subcortical regions as well. Furthermore, given the heterogeneity of behavioral symptoms in schizophrenia, it is not surprising that subsequent studies have shown other microscopic changes in schizophrenia including changes in cell size and number, changes in microglia (see review by Bakshshi and Chance, 2015), and evidence that abnormalities in other transmitters, especially glutamate, are also involved (McCutcheon et al., 2020). ...
Our understanding of the organization of the frontal cortex can be traced back to the experimental studies in the late 1800s by Fritsch and Hitzig on the frontal cortex of dogs and the frontal cortex of monkeys by Ferrier. These studies and many other studies that followed focused on motor functions, but halfway through the 20th century, very little was understood about the role of the frontal lobe in the control of other functions, and it was generally thought that the frontal lobe did not play a significant role in cognition. One result was that studies of cortical functions in cognition were carried out largely on parietal and temporal cortical regions with surprisingly little interest in the frontal lobe. The first systematic studies of the effects of prefrontal lesions on non-human primates began around 1950, especially by Rosvold and Mishkin in the Laboratory of Psychology at the National Institute of Mental Health (NIMH) in the United States. With her background in development, Pat Goldman joined this laboratory in 1965 and began an examination of the effects of prefrontal lobectomy on behavior in infant rhesus monkeys, both during development and later as the animals grew into adulthood. Her developmental studies were groundbreaking as they demonstrated that the effects of early prefrontal lesions varied with precise age (including prenatal), precise lesion location, behaviors measured, and age at assessment. She also began in parallel extensive studies of the role of the prefrontal cortex for a range of functions (especially working memory) in adult monkeys, which led to an examination of factors that influenced functional outcomes after injury or disease. This research was critical in helping to identify the significant role of the prefrontal cortex in cognition in both normal brains and neurological diseases such as schizophrenia. Her pioneering study demonstrating the role of the prefrontal cortex in cognition led to a remarkable increase in the number of researchers studying prefrontal functions in both non-human primates and rodents. This review will chronicle the key findings in her 35⁺ years studying the prefrontal cortex and illustrate the course she set for generations to follow.
... Here, we demonstrate that in male mice, conditionally targeting mC4 overexpression to PV cells leads to a drastic loss of excitatory drive on this inhibitory cell type that is accompanied by increased inhibition. Several lines of evidence point to synaptic dysfunction and pathological excitatory synaptic loss as prominent features of SCZ (22,(78)(79)(80). In support of this, our group previously demonstrated that increased levels of C4 in L2/3 mPFC PYRs is sufficient to cause a significant loss of excitatory synapses during early postsynaptic development, leading to mPFC circuit dysfunction (34). ...
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.
... and SZ, what has been evidenced by loss of dendritic spines and dendrites or decreased synapse number. [50][51][52] In this sense, a reduced expression of Egr1, considering it controls several other genes and, ultimately, entire biological pathways, may contribute to the impaired synaptic plasticity reported in psychiatric disorders. ...
Objectives:
To evaluate relative expression of genes with the potential to translate environmental stimuli into long-term alterations in the brain - namely Early Growth Response (EGR)1, EGR3, and Cryptochrome Circadian Regulator 2 (CRY2) - in peripheral blood from patients with Bipolar Disorder (BD), Schizophrenia (SZ), Major Depressive Disorder (MDD) and healthy controls (HC).
Methods:
Thirty individuals ranging from 18 to 60 years were recruited for each group (BD, SZ, MDD or HC) from a Brazilian public hospital. Therefore, individuals' peripheral blood was collected and EGR1, EGR3 and CRY2 gene expression analyzed by PCR Real Time.
Results:
EGR1 mRNA levels are significantly lower in psychiatric patients when compared to HC, but there is no difference for EGR3 and CRY2. Exploring the findings for each diagnosis, there is a significant difference between each diagnosis group only for EGR1, which was lower in BD, MDD and SZ as compared to HC. No significant correlations were found between gene expression and clinical features.
Conclusions:
EGR1 is downregulated in psychiatric patients, regardless of the diagnosis and may be a potential common target in major psychiatric disorders. EGR1, as a transcription factor, modulates many other genes and participates in crucial neuronal and synaptic processes, such as plasticity, neurotransmitters metabolism, vesicular transport and signaling pathways. The study of EGR1 and its upstream regulators in psychiatry might lead to potential new therapeutic targets.
... Altered dendritic arbor morphology and dendritic spine abnormalities are hallmarks of NDDs (69)(70)(71)(72)(73)(74)(75); for instance, spine density is greater in ASD and decreased in SCZ and BPD (76)(77)(78)(79). ...
Heterozygosity for rare genetic variants in TRIO is associated with neurodevelopmental disorders (NDDs) including schizophrenia (SCZ), autism spectrum disorder (ASD) and intellectual disability. TRIO uses its two guanine nucleotide exchange factor (GEF) domains to activate GTPases (GEF1: Rac1 and RhoG; GEF2: RhoA) that control neuronal migration, synapse development and function. It remains unclear whether and how discrete TRIO variants differentially impact these neurodevelopmental events. Here, we elucidate how heterozygosity for NDD-associated Trio variants – +/K1431M (ASD), +/K1918X (SCZ), and +/M2145T (bipolar disorder, BPD) – impact mouse behavior, brain development, and synapse structure and function. Heterozygosity for different Trio variants impacts motor, social, and cognitive behaviors in distinct ways that align with clinical phenotypes in humans. ASD- and SCZ-linked Trio variants differentially impact head and brain size with corresponding changes in dendritic arbors of motor cortex layer 5 pyramidal neurons (M1 L5 PNs). Although dendritic spine density and synaptic ultrastructure were only modestly altered in the Trio variant heterozygotes, we observe significant changes in synaptic function and plasticity including excitatory/inhibitory imbalance and long-term potentiation defects. We also identify distinct changes in glutamate synaptic release in +/K1431M and +/M2145T cortico-cortical synapses, associated with deficiencies in crucial presynaptic release regulators. While TRIO K1431M has impaired ability to promote GTP exchange on Rac1, +/K1431M mice exhibit increased Rac1 activity, suggesting possible compensation by other GEFs. Our work reveals that discrete disease-associated Trio variants yield overlapping but distinct NDD-associated phenotypes in mice and demonstrates, for the first time, an essential role for Trio in presynaptic glutamate release, underscoring the importance of studying the impact of variant heterozygosity in vivo.
... However, lentinan treatment abrogated these transcriptome changes. Numerous studies have reported the disruption of neurite arborization and synaptic plasticity in neurodegenerative disorders [60,61] and toxoplasmosis [4]. For example, T. gondii infection is reported to Liu et al. ...
Background
Toxoplasma gondii (T. gondii) is increasingly considered a risk factor for neurodegenerative diseases. However, there is only limited information on the development of drugs for T. gondii infection. Lentinan from Lentinula edodes is a bioactive ingredient with the potential to enhance anti-infective immunity. The present study aimed to investigate the neuroprotective effect of lentinan on T. gondii-associated cognitive deficits in mice.
Methods
A chronic T. gondii infection mouse model was established by administering 10 cysts of T. gondii by gavage. Lentinan was intraperitoneally administered 2 weeks before infection. Behavioral tests, RNA sequencing, immunofluorescence, transmission electron microscopy and Golgi-Cox staining were performed to assess the effect of lentinan on cognitive deficits and neuropathology in vivo. In vitro, the direct and indirect effects of lentinan on the proliferation of T. gondii tachyzoites were evaluated in the absence and presence of BV-2 cells, respectively.
Results
Lentinan prevented T. gondii-induced cognitive deficits and altered the transcriptome profile of genes related to neuroinflammation, microglial activation, synaptic function, neural development and cognitive behavior in the hippocampus of infected mice. Moreover, lentinan reduced the infection-induced accumulation of microglia and downregulated the mRNA expression of proinflammatory cytokines. In addition, the neurite and synaptic ultrastructural damage in the hippocampal CA1 region due to infection was ameliorated by lentinan administration. Lentinan decreased the cyst burden in the brains of infected mice, which was correlated with behavioral performance. In line with this finding, lentinan could significantly inhibit the proliferation of T. gondii tachyzoites in the microglial cell line BV2, although lentinan had no direct inhibitory effect on parasite growth.
Conclusions
Lentinan prevents cognitive deficits via the improvement of neurite impairment and synaptic loss induced by T. gondii infection, which may be associated with decreased cyst burden in the brain. Overall, our findings indicate that lentinan can ameliorate T. gondii-related neurodegenerative diseases.
Graphical Abstract
... Post-mortem studies have revealed reduced dendritic spine density in the cortices of patients with SZ, suggesting that synaptic deficits are a potential cause of SZ [89]. Synapses from patients with SZ exhibit heightened susceptibility to microglial phagocytosis compared to healthy controls. ...
Neurodevelopmental disorders (NDDs) include various neurological disorders with high genetic heterogeneity, characterized by delayed or impaired cognition, communication, adaptive behavior, and psychomotor skills. These disorders result in significant morbidity for children, thus burdening families and healthcare/educational systems. However, there is a lack of early diagnosis and effective therapies. Therefore, a more connected approach is required to explore these disorders. Microglia, the primary phagocytic cells within the central nervous system, are crucial in regulating neuronal viability, influencing synaptic dynamics, and determining neurodevelopmental outcomes. Although the neurobiological basis of autism spectrum disorder (ASD) and schizophrenia (SZ) has attracted attention in recent decades, the role of microglia in ASD and SZ remains unclear and requires further discussion. In this review, the important and frequently multifaceted roles that microglia play during neurodevelopment are meticulously emphasized and potential microglial mechanisms that might be involved in conditions such as ASD and SZ are postulated. It is of utmost importance to acquire a comprehensive understanding of the complexities of the interplay between microglia and neurons to design effective, targeted therapeutic strategies to mitigate the effects of NDDs.
... A principal pathological finding in postmortem studies of SZ patient brains is cortical thinning and reduced dendritic spine density on cortical pyramidal neurons [6][7][8]. Additionally, a recent positron emission tomography (PET) imaging study utilizing a probe for the synaptic vesicle protein SV2A, located exclusively at presynaptic terminals, found that patients with schizophrenia exhibit decreased brain synaptic density compared to healthy individuals [9]. These reductions in synapse density could result from excessive glial cell phagocytosis and have led to the hypothesis that dysregulated synaptic pruning may underlie schizophrenia pathogenesis. ...
Schizophrenia is a debilitating condition necessitating more efficacious therapies. Previous studies suggested that schizophrenia development is associated with aberrant synaptic pruning by glial cells. We pursued an interdisciplinary approach to understand whether therapeutic reduction in glial cell—specifically astrocytic—phagocytosis might benefit neuropsychiatric patients. We discovered that beta-2 adrenergic receptor (ADRB2) agonists reduced phagocytosis using a high-throughput, phenotypic screen of over 3200 compounds in primary human fetal astrocytes. We used protein interaction pathways analysis to associate ADRB2, to schizophrenia and endocytosis. We demonstrated that patients with a pediatric exposure to salmeterol, an ADRB2 agonist, had reduced in-patient psychiatry visits using a novel observational study in the electronic health record. We used a mouse model of inflammatory neurodegenerative disease and measured changes in proteins associated with endocytosis and vesicle-mediated transport after ADRB2 agonism. These results provide substantial rationale for clinical consideration of ADRB2 agonists as possible therapies for patients with schizophrenia.
Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimer’s disease, and have been correlated with kynurenine inflammatory signaling. Kynurenine is further metabolized to kynurenic acid (KYNA) in brain, where it blocks NMDA and α7-nicotinic receptors (nic-α7Rs). These receptors are essential for neurotransmission in dlPFC, suggesting that KYNA may cause higher cognitive deficits in these disorders. The current study found that KYNA and its synthetic enzyme, KAT II, have greatly expanded expression in primate dlPFC in both glia and neurons. Local application of KYNA onto dlPFC neurons markedly reduced the delay-related firing needed for working memory via actions at NMDA and nic-α7Rs, while inhibition of KAT II enhanced neuronal firing in aged macaques. Systemic administration of agents that reduce KYNA production similarly improved cognitive performance in aged monkeys, suggesting a therapeutic avenue for the treatment of cognitive deficits in neuroinflammatory disorders.
Schizophrenia is a disorder that begins at a young age and causes severe mortality and morbidity. The aetiology and pathophysiology of schizophrenia are still not known precisely. It is a very complex syndrome, and it is thought that more than one aetiological factor plays a role in its emergence. Genetics, epigenetics, and environmental and gene-environment interaction play a role in the aetiology of the disease. In addition, post-mortem neuropathological findings, neuroimaging findings, neurochemical studies, neuropsychological study results, and neurophysiological study results shed light on the mechanisms that cause the disease to occur. This chapter will provide an overview of the diathesis-stress, neurodegeneration, and neurodevelopmental models and summarise the work done so far in many areas.
Importance
The risk of mental disorders is consistently associated with variants in CACNA1C (L-type calcium channel Cav1.2) but it is not known why these channels are critical to cognition, and whether they affect the layer III pyramidal cells in the dorsolateral prefrontal cortex that are especially vulnerable in cognitive disorders.
Objective
To examine the molecular mechanisms expressed in layer III pyramidal cells in primate dorsolateral prefrontal cortices.
Design, Setting, and Participants
The design included transcriptomic analyses from human and macaque dorsolateral prefrontal cortex, and connectivity, protein expression, physiology, and cognitive behavior in macaques. The research was performed in academic laboratories at Yale, Harvard, Princeton, and the University of Pittsburgh. As dorsolateral prefrontal cortex only exists in primates, the work evaluated humans and macaques.
Main Outcomes and Measures
Outcome measures included transcriptomic signatures of human and macaque pyramidal cells, protein expression and interactions in layer III macaque pyramidal cells using light and electron microscopy, changes in neuronal firing during spatial working memory, and working memory performance following pharmacological treatments.
Results
Layer III pyramidal cells in dorsolateral prefrontal cortex coexpress a constellation of calcium-related proteins, delineated by CALB1 (calbindin), and high levels of CACNA1C (Cav1.2), GRIN2B (NMDA receptor GluN2B), and KCNN3 (SK3 potassium channel), concentrated in dendritic spines near the calcium-storing smooth endoplasmic reticulum. L-type calcium channels influenced neuronal firing needed for working memory, where either blockade or increased drive by β1-adrenoceptors, reduced neuronal firing by a mean (SD) 37.3% (5.5%) or 40% (6.3%), respectively, the latter via SK potassium channel opening. An L-type calcium channel blocker or β1-adrenoceptor antagonist protected working memory from stress.
Conclusions and Relevance
The layer III pyramidal cells in the dorsolateral prefrontal cortex especially vulnerable in cognitive disorders differentially express calbindin and a constellation of calcium-related proteins including L-type calcium channels Cav1.2 ( CACNA1C ), GluN2B-NMDA receptors ( GRIN2B ), and SK3 potassium channels ( KCNN3 ), which influence memory-related neuronal firing. The finding that either inadequate or excessive L-type calcium channel activation reduced neuronal firing explains why either loss- or gain-of-function variants in CACNA1C were associated with increased risk of cognitive disorders. The selective expression of calbindin in these pyramidal cells highlights the importance of regulatory mechanisms in neurons with high calcium signaling, consistent with Alzheimer tau pathology emerging when calbindin is lost with age and/or inflammation.
BACKGROUND
Brain-derived neurotrophic factor (BDNF) has considerable relevance in neural growth and differentiation. It has been evaluated as a biomarker for individuals with various psychiatric disorders such as substance-related disorders and psychotic disorders.
OBJECTIVE
The present study explored differences in the levels of BDNF (in serum) among subjects using cannabis (with and without schizophrenia).
METHODS
This cross-sectional observational study compared the serum BDNF level in male subjects aged 18–45 years. Four groups of 20 subjects each were included: individuals with tobacco use disorder only, patients having schizophrenia, patients with cannabis use disorder, and finally patients with comorbid cannabis use disorder and schizophrenia.
RESULTS
The BDNF levels were found to be significantly different across the four groups. The BDNF levels in subjects with concurrent schizophrenia and cannabis use disorder were higher than each of the other three groups (cannabis use disorder, schizophrenia, and tobacco use disorder only).
CONCLUSION
We find that BDNF may be higher when cannabis use disorder and schizophrenia co-occur, as compared to either of the conditions alone. The findings should be interpreted with caution due to the low sample size and potential confounders.
Disorders of behavior represent some of the most common and disabling diseases affecting humankind; however, despite their worldwide distribution, genetic influences on these illnesses are often overlooked by families and mental health professionals. Psychiatric genetics is a rapidly advancing field, elucidating the varied roles of specific genes and their interactions in brain development and dysregulation. Principles of Psychiatric Genetics includes 22 disorder-based chapters covering, amongst other conditions, schizophrenia, mood disorders, anxiety disorders, Alzheimer's disease, learning and developmental disorders, eating disorders and personality disorders. Supporting chapters focus on issues of genetic epidemiology, molecular and statistical methods, pharmacogenetics, epigenetics, gene expression studies, online genetic databases and ethical issues. Written by an international team of contributors, and fully updated with the latest results from genome-wide association studies, this comprehensive text is an indispensable reference for psychiatrists, neurologists, psychologists and anyone involved in psychiatric genetic studies.
Golgi methods were used to study human neuropathology in the 1970s, 1980s, and 1990s of the last century. Although a relatively small number of laboratories applied these methods, their impact was crucial by increasing knowledge about: (1) the morphology, orientation, and localization of neurons in human cerebral and cerebellar malformations and ganglionic tumors, and (2) the presence of abnormal structures including large and thin spines (spine dysgenesis) in several disorders linked to mental retardation, focal enlargements of the axon hillock and dendrites (meganeurites) in neuronal storage diseases, growth cone-like appendages in Alzheimer disease, as well as abnormal structures in other dementias. Although there were initial concerns about their reliability, reduced dendritic branches and dendritic spines were identified as common alterations in mental retardation, dementia, and other pathological conditions. Similar observations in appropriate experimental models have supported many abnormalities that were first identified using Golgi methods in human material. Moreover, electron microscopy, immunohistochemistry, fluorescent tracers, and combined methods have proven the accuracy of pioneering observations uniquely visualized as 3D images of fully stained individual neurons. Although Golgi methods had their golden age many years ago, these methods may still be useful complementary tools in human neuropathology.
Neurological and mental diseases, such as schizophrenia, Alzheimer’s disease, bipolar disorder, Parkinson’s disease, have complex phenotypes with cognitive impairment. These diseases are socially significant pathologies and serious problems for world health and are distinguished by the multilevel nature of the implementation of genetic information. A number of active genes are involved in the formation of the final phenotype. Thereby, it is necessary to apply the analysis of biological networks aimed at identifying the interacting genes and proteins that lead to the pathogenesis of the disease, in order to understand the molecular mechanisms underlying the studied pathology. In this study, various online resources and databases were used to implement this approach: WebGestalt, Gene Ontology, STRING. The protein-protein interaction network was obtained, where two subnets are distinguished, one of which is involved in the risk of developing schizophrenia, and the other in the risk of developing Alzheimer’s disease.
Mismatch negativity (MMN) to pitch (pMMN) and to duration (dMMN) deviant stimuli is significantly more attenuated in long-term psychotic illness compared to first-episode psychosis (FEP). It was recently shown that source-modeling of magnetically recorded MMN increases the detection of left auditory cortex MMN deficits in FEP, and that computational circuit modeling of electrically recorded MMN also reveals left-hemisphere auditory cortex abnormalities. Computational modeling using dynamic causal modeling (DCM) can also be used to infer synaptic activity from EEG-based scalp recordings. We measured pMMN and dMMN with EEG from 26 FEP and 26 matched healthy controls (HCs) and used a DCM conductance-based neural mass model including α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, N-methyl-D-Aspartate (NMDA), and Gamma-aminobutyric acid receptors to identify any changes in effective connectivity and receptor rate constants in FEP. We modeled MMN sources in bilateral A1, superior temporal gyrus, and inferior frontal gyrus (IFG). No model parameters distinguished groups for pMMN. For dMMN, reduced NMDA receptor activity in right IFG in FEP was detected. This finding is in line with literature of prefrontal NMDA receptor hypofunction in chronic schizophrenia and suggests impaired NMDA-induced synaptic plasticity may be present at psychosis onset where scalp dMMN is only moderately reduced. To the best of our knowledge, this is the first report of impaired NMDA receptor activity in FEP found through computational modeling of dMMN and shows the potential of DCM to non-invasively reveal synaptic-level abnormalities that underly subtle functional auditory processing deficits in early psychosis.
Complement is an important component of innate immune defence against pathogens and crucial for efficient immune complex disposal. These core protective activities are dependent in large part on properly regulated complement-mediated inflammation. Dysregulated complement activation, often driven by persistence of activating triggers, is a cause of pathological inflammation in numerous diseases, including neurological diseases. Increasingly, this has become apparent not only in well-recognized neuroinflammatory diseases like multiple sclerosis but also in neurodegenerative and neuropsychiatric diseases where inflammation was previously either ignored or dismissed as a secondary event. There is now a large and rapidly growing body of evidence implicating complement in neurological diseases that cannot be comprehensively addressed in a brief review. Here, we will focus on neurodegenerative diseases, including not only the ‘classical’ neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, but also two other neurological diseases where neurodegeneration is a neglected feature and complement is implicated, namely, schizophrenia, a neurodevelopmental disorder with many mechanistic features of neurodegeneration, and multiple sclerosis, a demyelinating disorder where neurodegeneration is a major cause of progressive decline. We will discuss the evidence implicating complement as a driver of pathology in these diverse diseases and address briefly the potential and pitfalls of anti-complement drug therapy for neurodegenerative diseases.
Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people’s cortical neurons and cortical astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22–97 years, including healthy individuals and people with schizophrenia. Latent-factor analysis of these data revealed that, in people whose cortical neurons more strongly expressed genes encoding synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the synaptic neuron and astrocyte program (SNAP). In schizophrenia and ageing—two conditions that involve declines in cognitive flexibility and plasticity1,2—cells divested from SNAP: astrocytes, glutamatergic (excitatory) neurons and GABAergic (inhibitory) neurons all showed reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy people of similar age, may underlie many aspects of normal human interindividual differences and may be an important point of convergence for multiple kinds of pathophysiology.
The study of brain connectivity has been a cornerstone in understanding the complexities of neurological and psychiatric disorders. It has provided invaluable insights into the functional architecture of the brain and how it is perturbed in disorders. However, a persistent challenge has been achieving the proper spatial resolution, and developing computational algorithms to address biological questions at the multi-cellular level, a scale often referred to as the mesoscale. Historically, neuroimaging studies of brain connectivity have predominantly focused on the macroscale, providing insights into inter-regional brain connections but often falling short of resolving the intricacies of neural circuitry at the cellular or mesoscale level. This limitation has hindered our ability to fully comprehend the underlying mechanisms of neurological and psychiatric disorders and to develop targeted interventions. In light of this issue, our review manuscript seeks to bridge this critical gap by delving into the domain of mesoscale neuroimaging. We aim to provide a comprehensive overview of conditions affected by aberrant neural connections, image acquisition techniques, feature extraction, and data analysis methods that are specifically tailored to the mesoscale. We further delineate the potential of brain connectivity research to elucidate complex biological questions, with a particular focus on schizophrenia and epilepsy. This review encompasses topics such as dendritic spine quantification, single neuron morphology, and brain region connectivity. We aim to showcase the applicability and significance of mesoscale neuroimaging techniques in the field of neuroscience, highlighting their potential for gaining insights into the complexities of neurological and psychiatric disorders.
Glutamatergic synapses are the primary site of excitatory synaptic signaling and neural communication in the cerebral cortex. Electron microscopy (EM) studies in non-human model organisms have demonstrated that glutamate synaptic activity and functioning are directly reflected in quantifiable ultrastructural features. Thus, quantitative EM analysis of glutamate synapses in ex vivo preserved human brain tissue has the potential to provide novel insight into in vivo synaptic functioning. However, factors associated with the acquisition and preservation of human brain tissue have resulted in persistent concerns regarding the potential confounding effects of antemortem and postmortem biological processes on synaptic and sub-synaptic ultrastructural features. Thus, we sought to determine how well glutamate synaptic relationships and nanoarchitecture are preserved in postmortem human dorsolateral prefrontal cortex (DLPFC), a region that substantially differs in size and architecture from model systems. Focused ion beam-scanning electron microscopy (FIB-SEM), a powerful volume EM (VEM) approach, was employed to generate high-fidelity, fine-resolution, three-dimensional (3D) micrographic datasets appropriate for quantitative analyses. Using postmortem human DLPFC with a 6-hour postmortem interval, we optimized a tissue preservation and staining workflow that generated samples of excellent ultrastructural preservation and the high-contrast staining intensity required for FIB-SEM imaging. Quantitative analysis of sub-cellular, sub-synaptic and organelle components within glutamate axo-spinous synapses revealed that ultrastructural features of synaptic function and activity were well-preserved within and across individual synapses in postmortem human brain tissue. The synaptic, sub-synaptic and organelle measures were highly consistent with findings from experimental models that are free from antemortem or postmortem effects. Further, dense reconstruction of neuropil revealed a unique, ultrastructurally-complex, spiny dendritic shaft that exhibited features characteristic of neuronal processes with heightened synaptic communication, integration and plasticity. Altogether, our findings provide a critical proof-of-concept that ex vivo VEM analysis provides a valuable and informative means to infer in vivo functioning of human brain.
Background and hypothesis:
Cognitive deficits in schizophrenia are linked to dysfunctions of the dorsolateral prefrontal cortex (DLPFC), including alterations in parvalbumin (PV)-expressing interneurons (PVIs). Redox dysregulation and oxidative stress may represent convergence points in the pathology of schizophrenia, causing dysfunction of GABAergic interneurons and loss of PV. Here, we show that the mitochondrial matrix protein cyclophilin D (CypD), a critical initiator of the mitochondrial permeability transition pore (mPTP) and modulator of the intracellular redox state, is altered in PVIs in schizophrenia.
Study design:
Western blotting was used to measure CypD protein levels in postmortem DLPFC specimens of schizophrenic patients (n = 27) and matched comparison subjects with no known history of psychiatric or neurological disorders (n = 26). In a subset of this cohort, multilabel immunofluorescent confocal microscopy with unbiased stereological sampling methods were used to quantify (1) numbers of PVI across the cortical mantle (20 unaffected comparison, 14 schizophrenia) and (2) PV and CypD protein levels from PVIs in the cortical layers 2-4 (23 unaffected comparison, 18 schizophrenia).
Study results:
In schizophrenic patients, the overall number of PVIs in the DLPFC was not significantly altered, but in individual PVIs of layers 2-4 PV protein levels decreased along a superficial-to-deep gradient when compared to unaffected comparison subjects. These laminar-specific PVI alterations were reciprocally linked to significant CypD elevations both in PVIs and total DLPFC gray matter.
Conclusions:
Our findings support previously reported PVI anomalies in schizophrenia and suggest that CypD-mediated mPTP formation could be a potential contributor to PVI dysfunction in schizophrenia.
Schizophrenia results in part from a failure of prefrontal networks but we lack full understanding of how disruptions at a synaptic level cause failures at the network level. This is a crucial gap in our understanding because it prevents us from discovering how genetic mutations and environmental risks that alter synaptic function cause prefrontal network to fail in schizophrenia. To address that question, we developed a recurrent spiking network model of prefrontal local circuits that can explain the link between NMDAR synaptic and 0-lag spike synchrony deficits we recently observed in a pharmacological monkey model of prefrontal network failure in schizophrenia. We analyze how the balance between AMPA and NMDA components of recurrent excitation and GABA inhibition in the network influence oscillatory spike synchrony to inform the biological data. We show that reducing recurrent NMDAR synaptic currents prevents the network from shifting from a steady to oscillatory state in response to extrinsic inputs such as might occur during behavior. These findings strongly parallel dynamic modulation of 0-lag spike synchrony we observed between neurons in monkey prefrontal cortex during behavior, as well as the suppression of this 0-lag spiking by administration of NMDAR antagonists. As such, our cortical network model provides a plausible mechanism explaining the link between NMDAR synaptic and 0-lag spike synchrony deficits observed in a pharmacological monkey model of prefrontal network failure in schizophrenia.
The increasing availability of high‐performance gradient systems in human MRI scanners has generated great interest in diffusion microstructural imaging applications such as axonal diameter mapping. Practically, sensitivity to axon diameter in diffusion MRI is attained at strong diffusion weightings , where the deviation from the expected scaling in white matter yields a finite transverse diffusivity, which is then translated into an axon diameter estimate. While axons are usually modeled as perfectly straight, impermeable cylinders, local variations in diameter (caliber variation or beading) and direction (undulation) are known to influence axonal diameter estimates and have been observed in microscopy data of human axons. In this study, we performed Monte Carlo simulations of diffusion in axons reconstructed from three‐dimensional electron microscopy of a human temporal lobe specimen using simulated sequence parameters matched to the maximal gradient strength of the next‐generation Connectome 2.0 human MRI scanner ( 500 mT/m). We show that axon diameter estimation is accurate for nonbeaded, nonundulating fibers; however, in fibers with caliber variations and undulations, the axon diameter is heavily underestimated due to caliber variations, and this effect overshadows the known overestimation of the axon diameter due to undulations. This unexpected underestimation may originate from variations in the coarse‐grained axial diffusivity due to caliber variations. Given that increased axonal beading and undulations have been observed in pathological tissues, such as traumatic brain injury and ischemia, the interpretation of axon diameter alterations in pathology may be significantly confounded.
Genome-wide association studies have revealed >270 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, few studies so far have profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects, or the effect of antipsychotic treatment on such epigenetic marks. Here we performed ChIP-seq and RNA-seq on frontal cortex samples from individuals with schizophrenia that were antipsychotic-free (AF) or antipsychotic-treated (AT), and individually matched controls (n=58). Schizophrenia subjects exhibited thousands of neuronal vs non-neuronal epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, DISC1, and DRD3. By analyzing the AF and AT cohorts separately, we identified schizophrenia-associated alterations in specific transcription factors, their regulatees, and epigenomic and transcriptomic features that were reversed by antipsychotic treatment; as well as those that represented a consequence of antipsychotic medication rather that a hallmark of schizophrenia in postmortem human brain samples. Notably, we also found that the effect of age on epigenomic landscapes was more pronounced in frontal cortex of AT-schizophrenics, as compared to AF-schizophrenics and controls. Together, these data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark for the first time the impact of age and antipsychotic treatment on chromatin organization.
Genome-wide association studies have revealed >270 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, few studies so far have profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects, or the effect of antipsychotic treatment on such epigenetic marks. Here we performed ChIP-seq and RNA-seq on frontal cortex samples from individuals with schizophrenia that were antipsychotic-free (AF) or antipsychotic-treated (AT), and individually matched controls (n=58). Schizophrenia subjects exhibited thousands of neuronal vs non-neuronal epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, DISC1, and DRD3. By analyzing the AF and AT cohorts separately, we identified schizophrenia-associated alterations in specific transcription factors, their regulatees, and epigenomic and transcriptomic features that were reversed by antipsychotic treatment; as well as those that represented a consequence of antipsychotic medication rather that a hallmark of schizophrenia in postmortem human brain samples. Notably, we also found that the effect of age on epigenomic landscapes was more pronounced in frontal cortex of AT-schizophrenics, as compared to AF-schizophrenics and controls. Together, these data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark for the first time the impact of age and antipsychotic treatment on chromatin organization.
Cambridge Textbook of Neuroscience for Psychiatrists is a 'one stop shop' for what any psychiatrist needs to know about the brain. Understanding the brain and mind requires a vast array of techniques and conceptual approaches. The Editors have assembled a team of basic neuroscientists, geneticists, psychologists, psychiatrists, neurologists, neurosurgeons and endocrinologists who bring you the cutting edge of translational neuroscience that addresses the material most relevant to current or future psychiatric practice. The book showcases what is known, highlights aspects that are less well understood and defines key outstanding questions. A revolution in our understanding of the brain has, so far, done little to disrupt mainstream psychiatric practice. That is set to change. The chapters align with the UK MRCPsych neuroscience syllabus and link to the USA National Neuroscience Curriculum Initiative (NNCI). Highly illustrated and accessible, this book will appeal to psychiatrists, neuroscientists, psychologists, other healthcare students and professionals.
Dendritic spine features in human neurons follow the up-to-date knowledge presented in the previous chapters of this book. Human dendrites are notable for their heterogeneity in branching patterns and spatial distribution. These data relate to circuits and specialized functions. Spines enhance neuronal connectivity, modulate and integrate synaptic inputs, and provide additional plastic functions to microcircuits and large-scale networks. Spines present a continuum of shapes and sizes, whose number and distribution along the dendritic length are diverse in neurons and different areas. Indeed, human neurons vary from aspiny or “relatively aspiny” cells to neurons covered with a high density of intermingled pleomorphic spines on very long dendrites. In this chapter, we discuss the phylogenetic and ontogenetic development of human spines and describe the heterogeneous features of human spiny neurons along the spinal cord, brainstem, cerebellum, thalamus, basal ganglia, amygdala, hippocampal regions, and neocortical areas. Three-dimensional reconstructions of Golgi-impregnated dendritic spines and data from fluorescence microscopy are reviewed with ultrastructural findings to address the complex possibilities for synaptic processing and integration in humans. Pathological changes are also presented, for example, in Alzheimer’s disease and schizophrenia. Basic morphological data can be linked to current techniques, and perspectives in this research field include the characterization of spines in human neurons with specific transcriptome features, molecular classification of cellular diversity, and electrophysiological identification of coexisting subpopulations of cells. These data would enlighten how cellular attributes determine neuron type-specific connectivity and brain wiring for our diverse aptitudes and behavior.
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Our hypothesis was that spiny stellate neurons in layer 4 of cat visual cortex receive polyneuronal innervation. We characterised the synapses of four likely sources of innervation by three simple criteria: the type of synapse, the target (spine, dendritic shaft), and the area of the presynaptic bouton. The layer 6 pyramids had the smallest boutons and formed asymmetric synapses mainly with the dendritic shaft. The thalamic afferents had the largest boutons and formed asymmetric synapses mainly with spines. The spiny stellates had medium-sized boutons and formed asymmetric synapses mainly with spines. We used these to make a "template" to match against the boutons forming synapses with the spiny stellate dendrite. Of the asymmetric synapses, 45% could have come from layer 6 pyramidal neurons, 28% from spiny stellate neurons, and 6% from thalamic afferents. The remaining 21% of asymmetric synapses could not be accounted for without assuming some additional selectivity of the presynaptic axons. Additional asymmetric synapses may come from a variety of sources, including other cortical neurons and subcortical nuclei such as the claustrum. Of the symmetric synapses, 84% could have been provided by clutch cells, which form large boutons. The remainder, formed by small boutons, probably come from other smooth neurons in layer 4, e.g., neurogliaform and bitufted neurons. Our analysis supports the hypothesis that the spiny stellate receives polyneuronal innervation, perhaps from all the sources of boutons in layer 4. Although layer 4 is the major recipient of thalamic afferents, our results show that they form only a few percent of the synapses of layer 4 spiny stellate neurons.
The pathophysiology of schizophrenia may involve perturbations of synaptic organization during development. The presence of cytoarchitectural abnormalities that may reflect such perturbations in the brains of patients with this disorder has been well-documented. Yet the mechanistic basis for these features of the disorder is still unknown. We hypothesized that altered regulation of the neuronal growth-associated protein GAP-43, a membrane phosphoprotein found at high levels in the developing brain, may play a role in the alterations in brain structure and function observed in schizophrenia. In the mature human brain, GAP-43 remains enriched primarily in association cortices and in the hippocampus, and it has been suggested that this protein marks circuits involved in the acquisition, processing, and/or storage of new information. Because these processes are known to be altered in schizophrenia, we proposed that GAP-43 levels might be altered in this disorder. Quantitative immunoblots revealed that the expression of GAP-43 is increased preferentially in the visual association and frontal cortices of schizophrenic patients, and that these changes are not present in other neuropsychiatric conditions requiring similar treatments. Examination of the levels of additional markers in the brain revealed that the levels of the synaptic vesicle protein synaptophysin are reduced in the same areas, but that the abundance of the astrocytic marker of neurodegeneration, the glial fibrillary acidic protein, is unchanged. In situ hybridization histochemistry was used to show that the laminar pattern of GAP-43 expression appears unaltered in schizophrenia. We propose that schizophrenia is associated with a perturbed organization of synaptic connections in distinct cortical associative areas of the human brain, and that increased levels of GAP-43 are one manifestation of this dysfunctional organization.
A pilot study of the density of dendritic spines on pyramidal neurons in layer III of human temporal and frontal cerebral neocortex in schizophrenia.
Postmortem material from a group of eight prospectively diagnosed schizophrenic patients, five archive schizophrenic patients, 11 non-schizophrenic controls, and one patient with schizophrenia-like psychosis, thought to be due to substance misuse, was impregnated with a rapid Golgi method. Spines were counted on the dendrites of pyramidal neurons in temporal and frontal association areas, of which the soma was in layer III (which take part in corticocortical connectivity) and which met strict criteria for impregnation quality. Altogether 25 blocks were studied in the schizophrenic group and 21 in the controls. If more than one block was examined from a single area, the counts for that area were averaged. All measurements were made blind: diagnoses were only disclosed by a third party after measurements were completed. Possible confounding affects of coexisting Alzheimer's disease were taken into account, as were the effects of age at death and postmortem interval.
There was a significant (p<0.001) reduction in the numerical density of spines in schizophrenia (276/mm in control temporal cortex and 112/mm in schizophrenic patients, and 299 and 101 respectively in the frontal cortex). An analysis of variance, taking out effects of age at death and postmortem interval, which might have explained the low spine density for some of the schizophrenic patients, did not affect the significance of the results.
The results support the concept of there being a defect in the fine structure of dendrites of pyramidal neurons, involving loss of spines, in schizophrenia and may help to explain the loss of cortical volume without loss of neurons in this condition, although the effect of neuroleptic drugs cannot be ruled out.
The randomness of the impregnation of layer IV cortical neurons by the Golgi-Cox method (Van der Loos, 1956) has been assessed directly in Barrel C-1 of the mouse SmI. All Golgi-Cox impregnated neurons and unimpregnated neurons which were revealed with Nissl counterstain were counted and measured in ten cerebral hemispheres cut tangential to the pia overlying the barrel field. The percentage of Golgi stained neurons varied considerably in different preparations from 0.73% to 2.26% with an average of 1.29%. The size distributions of both the Golgi impregnated and Nissl stained cells are similar but the difference of the means is statistically significant. However, if the means are eqated there is no statistical difference in the two populations. When the Golgi precipitate is removed and the cells re-measured following Nissl staining there is a systematic reduction of the perikaryal cross-sectional area which is compatible with the differences in the means observed for the two populations as a whole. Finally, the frequency with which Golgi impregnated neurons are found in the barrel sides and hollows parallels the frequency with which Nissl stained neurons are observed in these two locations. We conclude that this variant of the Golgi method impregnates barrel neurons randomly. The value of this information for quantitative studies of cerebral cortex is discussed as is the potential of the system for elucidating some of the mechanisms responsible for Golgi impregnation.
An understanding of the normal organization of prefrontal cortex is essential to the recognition of pathology underlying human behavioral disorders believed to depend on this region. We have therefore studied the pattern of intrinsic intra- and interlaminar pyramidal neuron connectivity in prefrontal areas 9 and 46 (of Walker) in macaque monkey cerebral cortex (anterior to the arcuate sulcus between the principal sulcus and midline). We made focal (200–400 μm) injections of biocytin and mapped the pattern of orthogradely transported label. Injections made into the superficial layers label wide-ranging lateral projections within the same areas of prefrontal cortex. Projections local to such small injections form a narrow band of terminals in layers 1–3 (200–400 μm wide, 2–4 mm long) centered on the injection site. Collateral fibers spread orthogonal to this terminal band, making frequent bifurcations, to establish a series of parallel bands of terminals with uninnervated bands between, spaced regularly across the cortex (center to center 500–600 μm). The entire pattern of terminal label is stripelike, with occasional narrower interbands and crosslinks between the bands, and can extend over 7–8 mm across the cortex. These projections arise from pyramidal neurons in layers 2, 3, and 5 and terminate in layers 1–3. The stripelike pattern contrasts with patchlike patterns in other cortical regions (V1, V2, V4, motor, somatosensory) and is smaller in scale than stripelike zones of corticocortical afferent terminals to this region, reported to be 300–750 μm wide and spaced 1.0–1.5 mm center to center. © 1993 Wiley-Liss, Inc.
The combined use of two anterograde axonal transport methods reveals that in the prefrontal association cortex of macaque
monkeys, associational projections from the parietal lobe of one hemisphere interdigitate with callosal projections from the
opposite frontal lobe, forming adjacent columns 300 to 750 micrometers wide. The finding of separate and alternating ipsilateral
and contralateral inputs in the frontal association cortex opens up new possibilities for the functional analysis of this
large but unexplored area of the primate brain.
Rats that consume a high-protein diet are hyperactive, hyperresponsive to noxious stimuli, and demonstrate elevated basal arousal levels. Although the mechanism involved in dietary protein-induced changes in behavior is unclear, it may involve many changes including abnormal dendrite morphology in the brain. Three groups of rats were pair-fed with isocaloric diets containing 8%, 20% and 50% casein for 4 weeks. Their brains were processed for examination of dendritic spine densities in the frontal, parietal, and entorhinal cortices, the striatum, and the septum. Animals on the 50% casein diet showed increased spine densities in all areas investigated (P less than 0.05), compared to the animals on normal (20%) casein. In contrast, animals maintained on the 8% casein diet showed increased spine densities (P less than 0.05) only in the striatum and entorhinal cortex, and exhibited normal densities in the frontal and parietal cortices, and the medial septum.
SEVERAL studies have reported that there is a loss of dendritic spines
after partial deafferentation. It is known that terminals lost to a
structure after injury to one of its afferents are replaced in part or
whole by sprouting of undamaged inputs1-3. This raises
questions as to the nature of the accompanying post-synaptic changes but
no attempts have been made to follow the loss of spines over
time4-6. Specifically, there are no data on whether spines
are replaced when sprouting afferents invade deafferented dendritic
zones. This is a critical question if the nature of the morphological
reorganisation which follows lesions in the brain is to be understood.
Dendritic spines disappear when the synaptic terminals impinging on them are destroyed. Terminal synaptic sites of axonal projections can be mapped by interrupting the afferent system and then comparing the density of dendrite spines in the suspected recipient area with controls. The corpus callosum was sectioned in five rabbits at birth. When the rabbits were 30 days old, the loss of dendrite spines was limited to the oblique branches of apical dendrites in the parietal cortex.
Postnatal development of the primate cerebral cortex involves an initial proliferation and the subsequent attrition of cortical synapses. Although these maturational changes in synaptic density have been observed across the cortical mantle, little is known about the precise time course of developmental refinements in synaptic inputs to specific populations of cortical neurons. We examined the postnatal development of two markers of excitatory and inhibitory inputs to a subpopulation of layer III pyramidal neurons in area 9 and 46 of rhesus monkey prefrontal cortex. These neurons are of particular interest because they play a major role in the flow of information both within and between cortical regions. Quantitative reconstructions of Golgi-impregnated mid-layer III pyramidal neurons revealed substantial developmental changes in the relative density of dendritic spines, the major site of excitatory inputs to these neurons. Relative spine density on both the apical and basilar dendritic trees increased by 50% during the first two postnatal months, remained at a plateau through 1.5 years of age, and then decreased over the peripubertal age range until stable adult levels were achieved. As a measure of the postnatal changes in inhibitory input to the axon initial segment of these pyramidal neurons, we determined the density of parvalbumin-immunoreactive axon terminals belonging to the chandelier class of local circuit neurons. The density of these distinctive axon terminals (cartridges) exhibited a temporal pattern of change that exactly paralleled the changes in dendritic spine density. These results suggest that subpopulations of cortical neurons may be regulated by dynamic interactions between excitatory and inhibitory inputs during development and, in concert with other data, they emphasize the cellular specificity of postnatal refinements in cortical circuitry.
A combined study of anterograde axonal degeneration and HRP retrograde labeling has shown that there exist monosynaptic connections between afferent fibers from the mediodorsal thalamic nucleus (MD) and callosal cells in the prelimbic cortex of the rat. Degenerating axon terminals from MD made asymmetrical synaptic contacts with dendritic spines from apical dendrites of layer III pyramidal cells that were retrogradely labeled with HRP after its injection into the prelimbic cortex contralateral to MD lesions.
The search for cellular correlates of learning is a major challenge in neurobiology. The hippocampal formation is important for learning spatial relations. A possible long-lasting consequence of such spatial learning is alteration of the size, shape, or number of excitatory synapses. The dendritic spine density is a good index for the number of hippocampal excitatory synapses. By using laser-scanning confocal microscopy, we observed a significantly increased spine density in CA1 basal dendrites of spatially trained rats when compared to nontrained controls. With unchanged dendritic length, the higher spine density reflects an increased number of excitatory synapses per neuron associated with spatial learning.
Since the turn of the century, the prefrontal association areas of the cerebral cortex have been thought to be among the last regions of the cortical mantle to develop. We have examined the course of synaptogenesis in the macaque prefrontal cortex by quantitative electron microscopic analysis in 25 rhesus monkeys ranging in age from embryonic day 47 (E47) to 20 years of age. A series of overlapping electron micrographs spanning the whole cortical thickness in each animal provided data on the number, the proportion, and the density of synapses per unit area (NA) and per unit volume (NV) of neuropil.
The tempo and kinetics of synapse formation in prefrontal cortex closely resemble those described for sensory and motor areas, particularly during the stages of synapse acquisition and overproduction (Rakic et al., 1986). In young embryos, we describe a precortical phase (E47-E78), when synapses are found only above and below, but not within, the cortical plate. Following that, there is an early cortical phase, from E78 to E104, during which synapses accumulate within the cortical plate, initially exclusively on dendritic shafts. The next rapid phase of synaptogenesis begins at 2 months before birth and ends approximately at 2 months after birth, culminating with a mean density of 750 million synapses per cubic micrometer. This accumulation is largely accounted for by a selective increase in axospine synapses in the supragranular layers. The period of explosive synaptic density is followed by a protracted plateau stage that lasts from 2 months to 3 years of age when synaptic density remains relatively constant. The final period of decline, from 3 years through over 20 years of age, is marked by a slight but statistically significant decline in synaptic density.
Concurrent recruitment of synapses with that of sensory and motor areas supports the concept that the initial establishment of cortical circuitry is governed by general mechanisms common to all areas, independent of their specific functional domain. The finding that synaptic density is relatively stable from early adolescence through puberty (the plateau period) is indicative of the importance, in primates, of a consistent and high synaptic density during the formative years when learning experiences are most intense.
Tachykinin-immunoreactive neurons are a subgroup of the GABA neuronal population in layer IVC of monkey primary visual cortex. Following brief periods of monocular deprivation in adult monkeys, immunoreactivity for both GABA and tachykinins is dramatically reduced in layer IV cells that lie within the deprived ocular dominance columns of this cortical area. The present study shows that these activity-dependent changes are associated with changes in mRNA levels but over different time courses. Radioactive antisense riboprobes derived from monkey-specific cDNAs were used to localize glutamic acid decarboxylase (GAD) and beta-preprotachykinin (beta PPT) mRNAs by in situ hybridization histochemistry. GAD and beta PPT mRNAs decreased in deprived ocular dominance columns of adult monkeys when neural activity was abolished in one eye by intraocular injections of tetrodotoxin (TTX). beta PPT mRNA levels fell within 5 d of deprivation and thus appeared to parallel the fall in immunodetectable tachykinin levels. By contrast, reduced GAD mRNA levels were detectable only after 15 d of deprivation and long after the fall in immunoreactive GAD and GABA levels has maximized. These results suggest that tachykinin gene expression is regulated by transcriptional mechanisms as part of the first response to reduced neural activity whereas the initial downregulation of immunoreactive GAD and GABA depends on posttranscriptional mechanisms. Following a more prolonged period of deprivation, a secondary mechanism for GAD regulation appears to be engaged at the level of gene transcription or possibly by changes in mRNA stability.
GABA neurons and GABA receptors are conspicuous elements of cerebral cortical organization. They serve to shape the stimulus-response
properties of neurons in the sensory areas and undoubtedly play a comparable role in the nonsensory areas as well. Although
nonGABAergic local circuit neurons exist in the cerebral cortex, the variety of forms adopted by the GABAergic neurons and
their important functional role have served to focus attention on the latter in investigations of local cortical circuitry.
In primate noocortex, GABAergic neurons constitute approximately 25–30% of the neuronal population. In addition to their known
or postulated functions in shaping neuronal receptive fields and response profiles, some of which are still controversial
(Sillito, 1984; Ferstar, 1986), their transmitter, GABA, and the major class of receptor upon which it acts are regulated
in an activity-dependent manner even in the adult (Jones, 1990). In this, there is a potential mechanism for the plasticity
of representational maps that is demonstrable in somatic sensory, motor, auditory, and visual cortex (Merzenich et al., 1983;
Sanes et al., 1988; Robertson and Irvine, 1989; Kaas at al., 1990).
Schizophrenia has been reported to be associated with alterations in GABAergic local circuit neurons of the prefrontal cortex. In this study, immunocytochemical techniques and antibodies against the calcium-binding proteins calbindin (CB) and calretinin (CR) were used to determine the laminar distribution and relative density of separate subpopulations of local circuit neurons in prefrontal cortical areas 9 and 46 from five pairs of schizophrenic and control subjects, matched for age, sex, and post-mortem interval. The laminar distribution pattern of CB-immunoreactive local circuit neurons was similar in both schizophrenic and control subjects. In both prefrontal regions, however, the density of CB-labeled neurons was 50-70% greater in schizophrenic subjects compared with control subjects, with cortical layers III and V/VI being preferentially affected. In contrast, the density of CR-IR neurons did not differ significantly between schizophrenic and control subjects. These findings reveal a selective increase in the density of a subpopulation of GABAergic local circuit neurons in the prefrontal cortex. Although other explanations for these observations must be considered, they may be consistent with the hypothesis that gene expression in GABAergic neurons is altered in schizophrenia.
Dynamic 133Xe single photon emission computed tomography (SPECT) was used to measure regional cerebral blood flow (rCBF) during the Wisconsin Card Sorting test (WCS) and the Number Matching task (NM) in six never-medicated first break schizophrenic and schizophreniform patients, seven chronic schizophrenic patients, and seven normal controls. Because of a difference in mean age between first break patients and normals, we adjusted rCBF data for age effects using ANCOVA. For age-adjusted absolute superior and middle frontal rCBF bilaterally, we found significantly less activation from NM to WCS in first break patients compared to normals. Similarly, for age-adjusted absolute and relative left middle frontal rCBF, we found significantly less activation in chronics compared to normals. Changes in age-adjusted global cerebral blood flow (gCBF) were not statistically significant among the three groups, but were in the same direction as activated absolute frontal rCBF. Because of the small number of subjects in each group, the results of this study should be regarded as preliminary and interpreted cautiously.
An impairment of prefrontal cortical functioning in schizophrenia ('hypofrontality') has been suggested by clinical, neuroimaging, and postmortem brain tissue studies. We used Western immunoblot and Northern hybridization analyses of postmortem brain tissue obtained from 14 schizophrenic patients and 12 control patients of similar ages to measure tissue levels of synaptophysin (a structural synaptic vesicle protein) and of SNAP-25 (a 25-kDa presynaptic protein), and their encoding mRNAs, in Brodmann's area 10 of prefrontal cortex. There were significant decreases in tissue levels of both of these proteins in prefrontal cortex of schizophrenic patients relative to controls. In contrast, tissue levels for the mRNAs encoding these proteins were not decreased in schizophrenic patients. Subsequent labeling of the same Western immunoblots showed no difference in tissue levels of glial fibrillary acidic protein (GFAP) in schizophrenic and control patients. Similarly, subsequent hybridization of the same Northern hybridization membranes showed no difference in tissue levels of GFAP mRNA or of 28S rRNA in schizophrenic and control patients. These alterations in tissue levels of synaptophysin and SNAP-25 are consistent with the idea that the clinically observed 'hypofrontality' of schizophrenia arises from abnormalities of synaptic number or structural integrity in prefrontal cortex.
Abnormalities of proteins involved in neurotransmission and neural plasticity at synapses are reported in schizophrenia, and may be markers of dysregulated neural connectivity in this illness. Studies of brain development and neural regeneration indicate a dynamic interplay between neural and oligodendroglial mechanisms in regulating synaptic plasticity and axonal sprouting. In the present study, markers of synapses (synaptophysin), plasticity (growth-associated protein-43) and oligodendrocytes (myelin basic protein) were investigated in anterior frontal cortex homogenates from individuals with schizophrenia and depression. Synaptophysin immunoreactivity was reduced in schizophrenics who died of natural causes relative to controls. Myelin basic protein immunoreactivity was decreased in both schizophrenics and depressed individuals who died by suicide. Overall, no changes were observed in growth-associated protein-43 immunoreactivity. However, a slight increase in immunoreactivity in depressed suicides relative to control was observed. These findings support the hypothesis that synaptic abnormalities are a substrate for disordered connectivity in severe mental illness, and suggest that synaptic-oligodendroglial interactions may contribute to the mechanism of dysregulation in certain cases.
Many patients with schizophrenia demonstrate memory deficits. We studied patterns of brain activity during episodic recognition of new and previously seen three-dimensional objects.
We used (15)O positron emission tomography to study regional cerebral blood flow in eight normal subjects and nine patients with schizophrenia during a visual object recognition task.
In comparison with control subjects, patients with schizophrenia showed less regional cerebral blood flow increases in the pulvinar region of the right thalamus and the right prefrontal cortex during the recognition of new objects and significantly greater left prefrontal cortex regional cerebral blood flow increases during the recognition of previously seen objects. Patients with schizophrenia exhibited alarm rates to new objects similar to those of control subjects, but significantly lower recognition rates for previously seen objects.
Schizophrenia is associated with attenuated right thalamic and right prefrontal activation during the recognition of novel visual stimuli and with increased left prefrontal cortical activation during impaired episodic recognition of previously seen visual stimuli. This study provides further evidence for abnormal thalamic and prefrontal cortex function in schizophrenia.