Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has been implicated in the pathophysiology of schizophrenia. The NMDAR contains a D-serine/glycine site on the NR1 subunit that may be a promising therapeutic target for psychiatric illness. This review outlines the complex regulation of endogenous NMDAR D-serine/glycine site agonists and explores their contribution to schizophrenia pathogenesis and their potential clinical utility. Genetic studies have associated genes influencing NMDAR D-serine/glycine site activation with an increased susceptibility to schizophrenia. Postmortem studies have identified abnormalities in several transcripts affecting D-serine/glycine site activity, consistent with in vivo reports of alterations in levels of endogenous D-serine/glycine site agonists and antagonists. Genetically modified mice with aberrant NMDAR D-serine/glycine site function model certain features of the negative and cognitive symptoms of schizophrenia, and similar behavioral abnormalities have been observed in other candidate genes models. Compounds that directly activate the NMDAR D-serine/glycine site or inhibit glycine transport have demonstrated beneficial effects in preclinical models and clinical trials. Future pharmacological approaches for schizophrenia treatment may involve targeting enzymes that affect D-serine synthesis and metabolism.
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PMID:The involvement of the NMDA receptor D-serine/glycine site in the pathophysiology and treatment of schizophrenia. 1969 84

Reduced function of the N-methyl-d-aspartate receptor (NMDAR) has been implicated in the pathophysiology of schizophrenia. The NMDAR contains a glycine binding site in its NR1 subunit that may be a useful target for the treatment of schizophrenia. In this study, we assessed the therapeutic potential of long-term increases in the brain levels of the endogenous NMDAR glycine site agonist D-serine, through the genetic inactivation of its catabolic enzyme D-amino acid oxidase (DAO) in mice. The effects of eliminating DAO function were investigated in mice that display schizophrenia-related behavioral deficits due to a mutation (Grin 1(D481N)) in the NR1 subunit that results in a reduction in NMDAR glycine affinity. Grin 1(D481N) mice show deficits in sociability, prolonged latent inhibition, enhanced startle reactivity and impaired spatial memory. The hypofunctional Dao 1(G181R) mutation elevated brain levels of D-serine, but alone it did not affect performance in the behavioral measures. Compared to animals with only the Grin 1(D481N) mutation, mice with both the Dao1(G181R) and Grin 1(D481N) mutations displayed an improvement in social approach and spatial memory retention, as well as a reversal of abnormally persistent latent inhibition and a partial normalization of startle responses. Thus, an increased level of D-serine resulting from decreased catalysis corrected the performance of mice with deficient NMDAR glycine site activation in behavioral tasks relevant to the negative and cognitive symptoms of schizophrenia. Diminished DAO activity and elevations in D-serine may serve as an effective therapeutic intervention for the treatment of psychiatric symptoms.
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PMID:Genetic loss of D-amino acid oxidase activity reverses schizophrenia-like phenotypes in mice. 1975 94

Phosphorylation of the NR1 subunit of NMDA receptors (NMDARs) at serine (S) 897 is markedly reduced in schizophrenia patients. However, the role of NR1 S897 phosphorylation in normal synaptic function and adaptive behaviors are unknown. To address these questions, we generated mice in which the NR1 S897 is replaced with alanine (A). This knock-in mutation causes severe impairment in NMDAR synaptic incorporation and NMDAR-mediated synaptic transmission. Furthermore, the phosphomutant animals have reduced AMPA receptor (AMPAR)-mediated synaptic transmission, decreased AMPAR GluR1 subunit in the synapse, and impaired long-term potentiation. Finally, the mutant mice exhibit behavioral deficits in social interaction and sensorimotor gating. Our results suggest that an impairment in NR1 phosphorylation leads to glutamatergic hypofunction that can contribute to behavioral deficits associated with psychiatric disorders.
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PMID:NMDA receptor phosphorylation at a site affected in schizophrenia controls synaptic and behavioral plasticity. 1977 82

Recently, neurotrophic factors and cytokines have been shown to be associated in psychiatric disorders, such as schizophrenia, bipolar disorder, and depression. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family, serves as a neurotrophic molecular and plays a significant role in the brain. We generated mice in which HB-EGF activity is disrupted specifically in the ventral forebrain. These knockout mice showed (a) behavioral abnormalities similar to those described in psychiatric disorders, which were ameliorated by typical or atypical antipsychotics, (b) altered dopamine and serotonin levels in the brain, (c) decreases in spine density in neurons of the prefrontal cortex, (d) reductions in the protein levels of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and post-synaptic protein-95 (PSD-95), (e) decreases in the EGF receptor, and in the calcium/calmodulin-dependent protein kinase II (CaMK II) signal cascade. These results suggest the alterations affecting HB-EGF signaling could comprise a contributing factor in psychiatric disorder.
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PMID:Generation and characterization of conditional heparin-binding EGF-like growth factor knockout mice. 1982 4

Several studies have shown the disruptive effects of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists on neurobehavioural development. Based on the neurodevelopment hypothesis of schizophrenia, there is growing interest in animal models treated with NMDA antagonists at developing stages to investigate the pathogenesis of psychological disturbances in humans. Previous studies have reported that perinatal treatment with phencyclidine (PCP) impairs the development of neuronal systems and induces schizophrenia-like behaviour. However, the adverse effects of prenatal exposure to PCP on behaviour and the function of NMDA receptors are not well understood. This study investigated the long-term effects of prenatal exposure to PCP in mice. The prenatal PCP-treated mice showed hypersensitivity to a low dose of PCP in locomotor activity and impairment of recognition memory in the novel object recognition test at age 7 wk. Meanwhile, the prenatal exposure reduced the phosphorylation of NR1, although it increased the expression of NR1 itself. Furthermore, these behavioural changes were attenuated by atypical antipsychotic treatment. Taken together, prenatal exposure to PCP produced long-lasting behavioural deficits, accompanied by the abnormal expression and dysfunction of NMDA receptors in postpubertal mice. It is worth investigating the influences of disrupted NMDA receptors during the prenatal period on behaviour in later life.
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PMID:Prenatal exposure to phencyclidine produces abnormal behaviour and NMDA receptor expression in postpubertal mice. 1983 58

The pathophysiology of schizophrenia may involve reduced NMDA receptor function and experimental models of NMDA receptor hypofunction have proven useful for characterizing neurobiological abnormalities potentially relevant to schizophrenia. The present study assessed behavioral responses and induction of Fos after administration of kainic acid to wild type mice (NR1(+/+)) and mice with genetically reduced NMDA receptor expression (NR1(neo/neo)). At a dose of 20 mg/kg, kainic acid induced lethal seizures in 100% of the NR1(neo/neo) mice tested but produced no lethal seizures in the wild type mice. The NR1(neo/neo) mice also exhibited enhanced behavioral responses to kainic acid at a dose of 15 mg/kg but no lethal seizures were produced by this dose. A greater induction of Fos was observed in neocortical and limbic cortical regions of the NR1(neo/neo) compared to NR1(+/+) mice after administration of 15 mg/kg kainic acid. In contrast, there were no differences between the genotypes in kainic acid induced Fos in the amygdala, hippocampus, lateral septum, and nucleus accumbens. In order to determine if altered behavioral phenotypes of the NR1(neo/neo) mice could be related to increased sensitivity of kainate receptors to endogenous glutamate, effects of the highly selective kainate antagonist LY382884 were examined. The kainate antagonist reduced the exaggerated acoustic startle responses, deficits in prepulse inhibition of acoustic startle, and motor hyperactivity in the NR1(neo/neo) mice. These findings suggest that selective kainate receptor antagonists could be novel therapeutic candidates for schizophrenia.
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PMID:Increased sensitivity to kainic acid in a genetic model of reduced NMDA receptor function. 1984 Jul 78

To determine if NMDA receptor alterations are present in the cerebellum in schizophrenia, we measured NMDA receptor binding and gene expression of the NMDA receptor subunits in a post-mortem study of elderly patients with schizophrenia and non-affected subjects. Furthermore, we assessed influence of genetic variation in the candidate gene neuregulin-1 (NRG1) on the expression of the NMDA receptor in an exploratory study. Post-mortem samples from the cerebellar cortex of ten schizophrenic patients were compared with nine normal subjects. We investigated NMDA receptor binding by receptor autoradiography and gene expression of the NMDA receptor subunits NR1, NR2A, NR2B, NR2C and NR2D by in situ hybridization. For the genetic study, we genotyped the NRG1 polymorphism rs35753505 (SNP8NRG221533). Additionally, we treated rats with the antipsychotics haloperidol or clozapine and assessed cerebellar NMDA receptor binding and gene expression of subunits to examine the effects of antipsychotic treatment. Gene expression of the NR2D subunit was increased in the right cerebellum of schizophrenic patients compared to controls. Individuals carrying at least one C allele of rs35753505 (SNP8NRG221533) showed decreased expression of the NR2C subunit in the right cerebellum, compared to individuals homozygous for the T allele. Correlation with medication parameters and the animal model revealed no treatment effects. In conclusion, increased NR2D expression results in a hyperexcitable NMDA receptor suggesting an adaptive effect due to receptor hypofunction. The decreased NR2C expression in NRG1 risk variant may cause a deficit in NMDA receptor function. This supports the hypothesis of an abnormal glutamatergic neurotransmission in the right cerebellum in the pathophysiology of schizophrenia.
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PMID:Gene expression of NMDA receptor subunits in the cerebellum of elderly patients with schizophrenia. 1985 12

Cortical GABAergic dysfunction may underlie the pathophysiology of psychiatric disorders, including schizophrenia. Here, we characterized a mouse strain in which the essential NR1 subunit of the NMDA receptor (NMDAR) was selectively eliminated in 40-50% of cortical and hippocampal interneurons in early postnatal development. Consistent with the NMDAR hypofunction theory of schizophrenia, distinct schizophrenia-related symptoms emerged after adolescence, including novelty-induced hyperlocomotion, mating and nest-building deficits, as well as anhedonia-like and anxiety-like behaviors. Many of these behaviors were exacerbated by social isolation stress. Social memory, spatial working memory and prepulse inhibition were also impaired. Reduced expression of glutamic acid decarboxylase 67 and parvalbumin was accompanied by disinhibition of cortical excitatory neurons and reduced neuronal synchrony. Postadolescent deletion of NR1 did not result in such abnormalities. These findings suggest that early postnatal inhibition of NMDAR activity in corticolimbic GABAergic interneurons contributes to the pathophysiology of schizophrenia-related disorders.
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PMID:Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. 2003 77

Recently a new category of treatment-responsive encephalitis has been proposed associated with antibodies against neuronal cell membrane antigens, including VGKC, NMDA receptor (NMDAR) and AMPA receptor. Anti-NMDAR encephalitis is caused by the antibodies, which bind to extracellular conformal epitope in the NR1/NR2 heteromers of the NMDAR. The antibodies are usually detected in CSF/serum of young women with ovarian teratoma (OT), who typically developed schizophrenia-like psychiatric symptoms. Most patients developed seizures, followed by unresponsive/catatonic state, central hypoventilation, and bizarre orofacial-limb dyskinesias. Based on symptomatology and current NMDAR hypofunction hypothesis in schizophrenia, we speculated that the antibodies might cause inhibition of NMDAR in presynaptic GABAergic interneurons, causing a reduction of release of GABA. This results in disinhibition of postsynaptic glutamatergic transmission, excessive release of glutamate in the prefrontal/subcortical structures, and glutamate/dopamine dysregulation. Recent studies demonstrated that the antibodies cause reversible reduction in the numbers of cell-surface NMDAR and NMDAR clusters in postsynaptic dendrites, suggesting antibodies-mediated decreased function of NMDAR. Early tumor resection with immunotherapy is recommended in OT-positive cases but not in OT-negative cases. However, exploratory laparotomy may increase the chance to identify microscopic teratoma and improve the outcome if patients who were refractory to immunotherapy had anti-NMDAR antibodies and ovarian cyst.
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PMID:[Unique clinical features and pathophysiology of anti-NMDA receptor encephalitis]. 2003 Feb 7

Several lines of evidence implicate aberrant glutamate neurotransmission in the pathophysiology of schizophrenia. In particular, compromised signaling through the N-methyl-D-aspartate (NMDA) receptor has been linked to positive, negative, and cognitive symptoms of this illness. Studies in postmortem brain have identified altered expression of several structural and signaling molecules of the postsynaptic density (PSD), including the abundantly expressed protein PSD-95, which binds directly to NR2 subunits of the NMDA receptor and regulates its trafficking, membrane expression, and downstream signaling. Several mechanisms for functional regulation of the NR2B-containing NMDA receptor, which have been linked to cognitive dysfunction in schizophrenia, are well known. To analyze whether early events in NR2B processing are affected in schizophrenia, we have isolated a subcellular endoplasmic reticulum (ER)-enriched fraction from postmortem brain and analyzed expression of the NR1 and NR2B NMDA receptor subunits as well as PSD-95 in two areas of prefrontal cortex. We found significantly decreased ER expression of NR2B and PSD-95 in dorsolateral prefrontal cortex in schizophrenia. Analysis in total-cell homogenates from the same subjects of NR2B and PSD-95 expression, as well as of the CINAP and Tbr-1 transcription regulatory proteins, indicate that changes in NR2B processing in schizophrenia involve increased ER exit of NR2B containing NMDA receptors.
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PMID:Expression of the NR2B-NMDA receptor subunit and its Tbr-1/CINAP regulatory proteins in postmortem brain suggest altered receptor processing in schizophrenia. 2017 24


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