Fig 8 - uploaded by Christine Konradi
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D 2 antagonists such as haloperidol facilitate NMDA receptor activity in the striatum by an intracellular mechanism. A: The medium-size spiny neurons in the striatum receive glutamate inputs from the cortex and dopamine inputs from the midbrain. Inhibition of D 2 receptors on the spiny neurons facilitates NMDA receptor activity and promotes a signal transduction pathway to the nucleus. B: D 2 antagonists activate an intracellular signal transduction pathway, including protein kinase A (PKA), which leads to the phosphorylation of the NR1 subtype of the NMDA receptor (Leveque et al., 2000). This phosphorylation increases the sensitivity of the NMDA receptor to glutamate and stimulates a signal transduction pathway that reaches the cell body. Gene expression enables the neuron to adjust its structure and function. Strong and persistent inhibition of D 2 receptors can overstimulate NMDA receptors and cause neurotoxicity. P, phosphate residue.
Source publication
The glutamate system is involved in many aspects of neuronal synaptic strength and function during development and throughout life. Synapse formation in early brain development, synapse maintenance, and synaptic plasticity are all influenced by the glutamate system. The number of neurons and the number of their connections are determined by the act...
Citations
... Specifically, according to the glutamate hypothesis, symptoms in schizophrenia may be linked to re duced functioning of NmethylDaspartate (NMDA) gluta mate receptors and excessive glutamate signalling. 196 This theory is in line with observations of the effects of NMDA receptor antagonists, such as ketamine, which can induce psychosis in healthy people. 197,198 Furthermore, postmortem studies showed lower levels of NMDA receptors in brains of patients with schizophrenia, compared with healthy con trols. ...
... 197,198 Furthermore, postmortem studies showed lower levels of NMDA receptors in brains of patients with schizophrenia, compared with healthy con trols. 196 Since NMDA receptors drive the activity of cortical inhibitory interneurons, a reduction in NMDA receptor function, as recorded in schizophrenia, reduces the rate of GABAergic interneurons, resulting in disinhibition of pyra midal neurons. 199 In addition, one of the most accepted and explored hypoth esis to explain the symptoms observed in schizophre nia is a state of hyperactive dopaminergic signal transduction within the nigrostriatal pathways. ...
The pathophysiology of schizophrenia and bipolar disorder involves a complex interaction between genetic and environmental factors that begins in the early stages of neurodevelopment. Recent advancements in the field of induced pluripotent stem cells (iPSCs) offer a promising tool for understanding the neurobiological alterations involved in these disorders and, potentially, for developing new treatment options. In this review, we summarize the results of iPSC-based research on schizophrenia and bipolar disorder, showing disturbances in neurodevelopmental processes, imbalance in glutamatergic–GABAergic transmission and neuromorphological alterations. The limitations of the reviewed literature are also highlighted, particularly the methodological heterogeneity of the studies, the limited number of studies developing iPSC models of both diseases simultaneously, and the lack of in-depth clinical characterization of the included samples. Further studies are needed to advance knowledge on the common and disease-specific pathophysiological features of schizophrenia and bipolar disorder and to promote the development of new treatment options.
... Even though the SNP is not located in the protein coding sequence, the proximity of this SNP to DRD2 in the genomic region has been shown to lower the number of DRD2 receptor (Doehring et al., 2009;Li et al., 2018a). While the genetic makeup of the dopaminergic system plays a significant role in the pathophysiology of SCZ, the intricate connection between the dopaminergic system and the glutamatergic system has prompted further exploration of the role of the glutamatergic system in the development of SCZ (Konradi and Heckers, 2003). ...
This review examines the substantial involvement of Single Nucleotide Polymorphisms (SNPs) and microRNAs (miRNAs) in the etiology and susceptibility to Schizophrenia, with particular emphasis on the dopaminergic, glutamatergic, and GABAergic systems. It elucidates the potential of SNPs to disrupt miRNA-mRNA interactions, leading to alterations in the regulatory mechanisms of Schizophrenia risk genes and subsequently influencing the susceptibility to Schizophrenia. Specific attention is given to the impact of SNPs in DICER, DROSHA, and DGCR8, as well as the potential for changes in DRD2 gene expression driven by miR-9 and miR-326, heightening the likelihood of Schizophrenia development. Furthermore, the review explores genetic alterations in the glutamatergic system, focusing on modifications linked to GRIN2A and its associated miRNAs, which have been reported to have a notable impact on the occurrence of Schizophrenia. Knowledge of the involvement of SNPs within miRNAs in influencing the expression of essential genes within the GABA system are emerging and described in this review, including their potential consequences for Schizophrenia.
... Excessive entry of Ca 2+ through the NMDA receptor is thought to be the major cause of glutamate toxicity in brain neurons [66]. Here, we have shown that NMDARs are involved in Glu toxicity in neuronal cell culture, consistent with previous reports [51,67]. ...
Serine proteases regulate cell functions through G protein-coupled protease-activated receptors (PARs). Cleavage of one peptide bond of the receptor amino terminus results in the formation of a new N-terminus (“tethered ligand”) that can specifically interact with the second extracellular loop of the PAR receptor and activate it. Activation of PAR1 by thrombin (canonical agonist) and activated protein C (APC, noncanonical agonist) was described as a biased agonism. Here, we have supposed that synthetic peptide analogs to the PAR1 tethered ligand liberated by APC could have neuroprotective effects like APC. To verify this hypothesis, a model of the ischemic brain impairment based on glutamate (Glu) excitotoxicity in primary neuronal cultures of neonatal rats has been used. It was shown that the nanopeptide NPNDKYEPF-NH2 (AP9) effectively reduced the neuronal death induced by Glu. The influence of AP9 on cell survival was comparable to that of APC. Both APC and AP9 reduced the dysregulation of intracellular calcium homeostasis in cultured neurons induced by excitotoxic Glu (100 µM) or NMDA (200 µM) concentrations. PAR1 agonist synthetic peptides might be noncanonical PAR1 agonists and a basis for novel neuroprotective drugs for disorders related to Glu excitotoxicity such as brain ischemia, trauma and some neurodegenerative diseases.
... Excessive entry of Ca2+ through the NMDA receptor is thought to be the major cause of glutamate toxicity in brain neurons [63]. Here we have shown that NMDARs are involved in Glutoxicity in cultural neurons, consistent with previous reports [48]. ...
Serine proteases regulate cell functions through G protein-coupled protease-activated receptors (PARs). Cleavage of one peptide bond of the receptor amino terminus results in the formation of a new N-terminus ("tethered ligand") that can specifically interact with the second extracellular loop of the PAR receptor and activate it. Activation of PAR1 by thrombin (canonical agonist) and activated protein C (APC, noncanonical agonist) was described as biased agonism. Here we have supposed that synthetic peptide analogues to the PAR1 tethered ligand liberated by APC could have neuroprotective effects like APC. To verify this hypothesis a model of the ischemic brain impairment based on glutamate (Glu) excitotoxicity in primary neuronal cultures of neonatal rats has been used. It was shown that nanopeptide NPNDKYEPF-NH2 (AP9) effectively reduced the neuronal death induced by Glu. The influence of AP9 on cell survival was comparable to that of APC. Both APC and AP9 reduced the dysregulation of intracellular calcium homeostasis in cultured neurons induced by excitotoxic Glu (100 µM) or NMDA (200 µM) concentrations. PAR1 agonist synthetic peptides might be a noncanonial PAR1-agonist and a basis of novel neuroprotective drugs for disorders related to Glu excitotoxicity such as brain ischemia, trauma and some neurodegenerative diseases.
... For example, PKA signaling increases AMPA receptor cell surface expression and trafficking in an activity-dependent manner in cortical neurons [23]. Moreover, dysregulated AMPA receptor expression and localization is reported in the frontal cortex in schizophrenia [24][25][26], a process that is correlated with altered synaptic plasticity and brain dysconnectivity: core phenomena observed in this disorder [23,27]. Additionally, PKA signaling induces transcription factor 4 (TCF4), a protein associated with cognitive deficits in schizophrenia, in cortical neurons [28]. ...
... The overactivity of the dopamine D 2 receptors, which are also GPCRs, contributes to the positive symptoms observed in schizophrenia and is correlated with PKA dysregulation [56]. Alterd glutamatergic signaling, which leads to the dysregulation of NMDA and AMPA receptors, also affects PKA activity [27,57]. The dysfunction of neuropeptide signaling pathways acting through GPCRs, such as neuropeptide Y or substance P, has also been implicated in schizophrenia and PKA signaling abnormalities [58]. ...
Schizophrenia is a serious cognitive disorder characterized by disruptions in neurotransmission, a process requiring the coordination of multiple kinase-mediated signaling events. Evidence suggests that the observed deficits in schizophrenia may be due to imbalances in kinase activity that propagate through an intracellular signaling network. Specifically, 3′-5′-cyclic adenosine monophosphate (cAMP)-associated signaling pathways are coupled to the activation of neurotransmitter receptors and modulate cellular functions through the activation of protein kinase A (PKA), an enzyme whose function is altered in the frontal cortex in schizophrenia. In this study, we measured the activity of PKA in human postmortem anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) tissue from schizophrenia and age- and sex-matched control subjects. No significant differences in PKA activity were observed in male and female individuals in either brain region; however, correlation analyses indicated that PKA activity in the ACC may be influenced by tissue pH in all subjects and by age and tissue pH in females. Our data provide novel insights into the function of PKA in the ACC and DLPFC in schizophrenia.
... The temporal dynamics of GLU and ACh after the first or second administration of vCOC and vMETH are lacking abrupt or extensive changes in concentration, as we have described for the monoamines. However, considering that GLU transmission is a primary contributor in the majority of neuroplastic processes related to abused substances in mammals [49], minor, but significant changes that we recorded after the first vCOC and vMETH administration could potentially have a similar impact on the modulation of specific neuronal networks in flies that are related to addiction endophenotypes. Since both GLU and Ach show moderate increases at the later time points after the first psychostimulant administration, it could indicate that these changes are driven by pharmacodynamics of the initial vCOC and vMETH monoaminergic targets. ...
Due to similarities in genetics, cellular response, and behavior, Drosophila is used as a model organism in addiction research. A well-described behavioral response examined in flies is the induced increase in locomotor activity after a single dose of volatilized cocaine (vCOC) and volatilized methamphetamine (vMETH), the sensitivity, and the escalation of the locomotor response after the repeated dose, the locomotor sensitization. However, knowledge about how vCOC and vMETH affect different neurotransmitter systems over time is scarce. We used LC-MS/MS to systematically examine changes in the concentration of neurotransmitters, metabolites and non-metabolized COC and METH in the whole head homogenates of male flies one to seven hours after single and double vCOC or vMETH administrations. vMETH leads to complex changes in the levels of examined substances over time, while vCOC strongly and briefly increases concentrations of dopamine, tyramine and octopamine followed by a delayed degradation into N-acetyl dopamine and N-acetyl tyramine. The first exposure to psychostimulants leads to significant and dynamic changes in the concentrations relative to the second administration when they are more stable over several hours. Further investigations are needed to understand neurochemical and molecular changes post-psychostimulant administration.
... The temporal dynamics of GLU and ACh after the first or second administration of vCOC and vMETH is lacking abrupt or extensive changes in concentration, as we have described for the monoamines. However, considering that GLU transmission is a primary contributor in the majority of neuroplastic processes related to abused substances in mammals [47], minor, but significant changes that we recorded after the first vCOC and vMETH administration could potentially have a similar impact on the modulation of specific neuronal networks in flies that are related to addiction endophenotypes. Since both GLU and ACh show moderate increases at the later time points after the first psychostimulant administration, it could indicate that these changes are driven by pharmacodynamics of the initial vCOC and vMETH monoaminergic targets. ...
Due to similarities in genetics, cellular response, and behavior, Drosophila is used as a model organism in addiction research. A well described behavioral response examined in flies is the induced increase in locomotor activity after a single dose of volatilized cocaine (vCOC) and volatilized methamphetamine (vMETH) known as sensitivity, and the escalation of the locomotor response after the repeated dose, known as the locomotor sensitization. However, knowledge about how vCOC and vMETH affect different neurotransmitter systems over time is scarce. We used LC-MS/MS to systematically examine changes in the concentration of neurotransmitters, metabolites and non-metabolized COC and METH in the whole head homogenates of male flies one to seven hours after single and double vCOC or vMETH administrations. vMETH leads to complex changes in the levels of examined substances over time, while vCOC strongly and briefly increases concentrations of dopamine, tyramine and octopamine followed by a delayed degradation into N-acetyl dopamine and N-acetyl tyramine. The first exposure to psychostimulants leads to significant and dynamic changes in the concentrations relative to the second administration when they are more stable over several hours. Further investigations are needed to understand neurochemical and molecular changes post-psychostimulant administration.
... Precisely, the administration of NMDA receptor antagonists, such as ketamine and phencyclidine, provides a favorable support for the theory of NMDA receptor hypofunction and impaired plasticity in people with schizophrenia (Coyle, 2006;Schmidt et al., 2012;Corlett et al., 2011), and these eventually lead to anterograde amnesia which further translates to poor learning ability and avolition behavior in mice. It has also been recently reported that; dysfunction of glutamatergic NMDA receptors with both a hypoglutamatergic and a periodic hyperglutamatergic state in schizophrenic patients has been evident (Paz et al., 2008;Konradi and Heckers, 2003;Paz et al., 2006). ...
... Studies have also shown that this excitotoxicity may be associated with a variety of psychiatric disorders, including schizophrenia (Plitman et al. 2014). This may also be due to a decrease in NMDA receptor activity in the cortical-brainstem projection area, thereby removing the activating effect of dopamine (Konradi and Heckers 2003). For another, increased activity of the dopaminergic pathway in the midbrain limb due to NMDA receptor underactivity also causes positive symptoms, which is consistent with the DA hypothesis centered on dysregulated dopamine levels (Konradi and Heckers 2003;Maksymetz et al. 2017). ...
... This may also be due to a decrease in NMDA receptor activity in the cortical-brainstem projection area, thereby removing the activating effect of dopamine (Konradi and Heckers 2003). For another, increased activity of the dopaminergic pathway in the midbrain limb due to NMDA receptor underactivity also causes positive symptoms, which is consistent with the DA hypothesis centered on dysregulated dopamine levels (Konradi and Heckers 2003;Maksymetz et al. 2017). ...
Schizophrenia is a devastating neuropsychiatric disorder affecting 1% of the world population and ranks as one of the disorders providing the most severe burden for society. Schizophrenia etiology remains obscure involving multi-risk factors, such as genetic, environmental, nutritional, and developmental factors. Complex interactions of genetic and environmental factors have been implicated in the etiology of schizophrenia. This review provides an overview of the historical origins, pathophysiological mechanisms, diagnosis, clinical symptoms and corresponding treatment of schizophrenia. In addition, as schizophrenia is a polygenic, genetic disorder caused by the combined action of multiple micro-effective genes, we further detail several approaches, such as candidate gene association study (CGAS) and genome-wide association study (GWAS), which are commonly used in schizophrenia genomics studies. A number of GWASs about schizophrenia have been performed with the hope to identify novel, consistent and influential risk genetic factors. Finally, some schizophrenia susceptibility genes have been identified and reported in recent years and their biological functions are also listed. This review may serve as a summary of past research on schizophrenia genomics and susceptibility genes (NRG1, DISC1, RELN, BDNF, MSI2), which may point the way to future schizophrenia genetics research. In addition, depending on the above discovery of susceptibility genes and their exact function, the development and application of antipsychotic drugs will be promoted in the future.
... Our in vitro electrophysiological analysis in brain slices of mice treated with JWH-018 revealed an impairment in LTP. Previous studies revealed that a single JWH-018 administration induced an impairment in short-(2 h) and longterm (24 h) working memory in mice (Barbieri et al., 2016;Barbieri et al., 2022;Li et al., 2019) At the molecular level, we first investigated the levels of the NMDA receptor, which is known to be altered in schizophrenic patients (Errico et al., 2013) and animal models of the disease (Konradi & Heckers, 2003;Oka et al., 2020;Wu et al., 2021). In striatum, we found that the expression of the three main subunits of the NMDA receptor, that is, the GluN1, GluN2A and GluN2B, are reduced in the crude striatal synaptosomal fraction, but not in the whole homogenate. ...
Background and Purpose
Psychotic disorders have been reported in long‐term users of synthetic cannabinoids. This study aims at investigating the long‐lasting effects of repeated JWH‐018 exposure.
Experimental Approach
Male CD‐1 mice were injected with vehicle, JWH‐018 (6 mg·kg⁻¹), the CB1‐antagonist NESS‐0327 (1 mg·kg⁻¹) or co‐administration of NESS‐0327 and JWH‐018, every day for 7 days. After 15 or 16 days washout, we investigated the effects of JWH‐018 on motor function, memory, social dominance and prepulse inhibition (PPI). We also evaluated glutamate levels in dialysates from dorsal striatum, striatal dopamine content and striatal/hippocampal neuroplasticity focusing on the NMDA receptor complex and the neurotrophin BDNF. These measurements were accompanied by in vitro electrophysiological evaluations in hippocampal preparations. Finally, we investigated the density of CB1 receptors and levels of the endocannabinoid anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG) and their main synthetic and degrading enzymes in the striatum and hippocampus.
Key Results
The repeated treatment with JWH‐018 induced psychomotor agitation while reducing social dominance, recognition memory and PPI in mice. JWH‐018 disrupted hippocampal LTP and decreased BDNF expression, reduced the synaptic levels of NMDA receptor subunits and decreased the expression of PSD95. Repeated exposure to JWH‐018, reduced hippocampal CB1 receptor density and induced a long‐term alteration in AEA and 2‐AG levels and their degrading enzymes, FAAH and MAGL, in the striatum.
Conclusion and Implications
Our findings suggest that repeated administration of a high dose of JWH‐018 leads to the manifestation of psychotic‐like symptoms accompanied by alterations in neuroplasticity and change in the endocannabinoid system.
