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)

Clinical trials demonstrated that D-serine administration improves schizophrenia symptoms, raising the possibility that altered levels of endogenous D-serine may contribute to the N-methyl D-aspartate receptor hypofunction thought to play a role in the disease. We hypothesized that cerebro-spinal fluid (CSF) D-serine levels are decreased in the patients due to reduced synthesis and/or increased degradation in brain. We now monitored amino acid levels in CSF from 12 schizophrenia patients vs. 12 controls and in postmortem parietal-cortex from 15 control subjects and 15 each of schizophrenia, major-depression and bipolar patients. In addition, we monitored postmortem brain serine racemase and D-amino acid oxidase protein levels by Western-blot analysis. We found a 25% decrease in D-serine levels and D/L-serine ratio in CSF of schizophrenia patients, while parietal-cortex D-serine was unaltered. Levels of L-serine, L-glutamine and L-glutamate were unaffected. Frontal-cortex (39%) and hippocampal (21%) serine racemase protein levels and hippocampal serine racemase/D-amino acid oxidase ratio (34%) were reduced. Hippocampal D-amino-acid-oxidase protein levels significantly correlated with duration of illness (r=0.6, p=0.019) but not age. D-amino acid oxidase levels in patients with DOI>20 years were 77% significantly higher than in the other patients and controls. Our results suggest that reduced brain serine racemase and elevated D-amino acid oxidase protein levels may contribute to the lower CSF D-serine levels in schizophrenia.
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PMID:A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia. 1715 77

Schizophrenia is noted for the remarkably high prevalence of substance use disorders (SUDs) including nicotine (>85%), alcohol and stimulants. Mounting evidence supports the hypothesis that the endophenotype of schizophrenia involves hypofunction of a subpopulation of cortico-limbic NMDA receptors. Low doses of NMDA receptor antagonists such as ketamine replicate in normal volunteers positive, negative and cognitive symptoms of schizophrenia as well as associated physiologic abnormalities such as eye tracking and abnormal event related potentials. Genetic studies have identified putative risk genes that directly or indirectly affect NMDA receptors including D-amino acid oxidase, its modulator G72, proline oxidase, mGluR3 and neuregulin. Clinical trials have shown that agents that directly or indirectly enhance the function of the NMDA receptor at its glycine modulatory site (GMS) reduce negative symptoms and in the case of D-serine and sarcosine improve cognition and reduce positive symptoms in schizophrenic subjects receiving concurrent anti-psychotic medications. Notably, the GMS partial agonist D-cycloserine exacerbates negative symptoms in clozapine responders whereas full agonists, glycine and D-serine have no effects, suggesting clozapine may act indirectly as a full agonist at the GMS of the NMDA receptor. Clozapine treatment is uniquely associated with decreased substance use in patients with schizophrenia, even without psychologic intervention. Given the role of NMDA receptors in the reward circuitry and in substance dependence, it is reasonable to speculate that NMDA receptor dysfunction is a shared pathologic process in schizophrenia and co-morbid SUDs.
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PMID:Substance use disorders and Schizophrenia: a question of shared glutamatergic mechanisms. 1719 72

Gliotransmission is a process in which astrocytes are dynamic elements that influence synaptic transmission and synaptogenesis. The best-known gliotransmitters are glutamate and ATP. However, in the past decade, it has been demonstrated that D-serine, a D-amino acid, acts as a gliotransmitter in glutamatergic synapses. The physiological relevance of D-serine is sustained by the way in which it modulates the action of glutamatergic neurotransmission, neuronal migration and long-term potentiation (LTP). In addition, the synthesis and degradation mechanisms of D-serine have been proposed as potential therapeutic targets for the treatment of Alzheimer's disease, schizophrenia and related disorders. In the present review, detailed information is provided about the physiological and physiopathological relevance of D-serine, including metabolic and regulation aspects.
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PMID:D-serine: a new word in the glutamatergic neuro-glial language. 1724 16

We review the role of two susceptibility genes; G72 and DAAO in glutamate neurotransmission and the aetiology of schizophrenia. The gene product of G72 is an activator of DAAO (D-amino acid oxidase), which is the only enzyme oxidising D-serine. D-serine is an important co-agonist for the NMDA glutamate receptor and plays a role in neuronal migration and cell death. Studies of D-serine revealed lower serum levels in schizophrenia patients as compared to healthy controls. Furthermore, administration of D-serine as add-on medication reduced the symptoms of schizophrenia. The underlying mechanism of the involvement of G72 and DAAO in schizophrenia is probably based on decreased levels of D-serine and decreased NMDA receptor functioning in patients. The involvement of this gene is therefore indirect support for the glutamate dysfunction hypothesis in schizophrenia.
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PMID:Reviewing the role of the genes G72 and DAAO in glutamate neurotransmission in schizophrenia. 1725 Sep 95

It has recently been suggested that neurogenesis in the dentate gyrus is decreased in schizophrenia and this phenomenon may contribute to the pathogenesis of the disorder. Since repeated administration of psychostimulants such as phencyclidine (PCP), MK-801, and methamphetamine (METH) induces schizophrenia-like behavioral changes in animals, we investigated whether repeated administration of these psychostimulants affects neurogenesis in the dentate gyrus of mice. Newborn cells were labeled by bromodeoxyuridine (BrdU) and detected by immunohistochemistry. Repeated administration of PCP and MK-801, but not METH, resulted in a decrease in the number of BrdU-labeled cells in the dentate gyrus. PCP-induced decrease in the number of BrdU-labeled cells was negated by co-administration of clozapine, but not haloperidol, although repeated antipsychotics treatment by themselves had no effect. Furthermore, co-administration of D-serine and glycine, but not L-serine, inhibited the PCP-induced decrease in the number of BrdU-labeled cells. These results suggest that chronic dysfunction of NMDA receptors causes a decrease in neurogenesis in the dentate gyrus.
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PMID:Clozapine prevents a decrease in neurogenesis in mice repeatedly treated with phencyclidine. 1734 43

A number of linkage studies have previously implicated the region of chromosome 13q34 in schizophrenia. Chumakov and colleagues (2002) identified a gene complex called G72 (now termed D-amino acid oxidase activator: DAOA)/G30 in this region and performed association analyses of the DAOA/G30 as well as the D-amino-acid oxidase (DAAO) gene with schizophrenia. DAAO oxidizes D-serine, a potent activator of the N-methyl-D-aspartate (NMDA) type glutamate receptor in the human brain whereas the DAOA protein is considered an activator of DAAO. The interaction of these two genes has thus been implicated in the NMDA receptor regulation pathway in schizophrenia. To date, several studies have shown a relatively consistent positive association between schizophrenia and DAOA/G30, but not with DAAO. The aim of our study was to further evaluate the contributions of these genes to the susceptibility to schizophrenia using two different sample sets. Our sample consisted of 168 matched case-control pairs as well as a family-based sample (n=113) for transmission disequilibrium test. Significant associations between the DAOA/G30 M-7 and M-18 polymorphisms and schizophrenia were observed in our case-control sample whereas no associations were observed for DAAO markers. We also observed significant or suggestive transmission disequilibrium for DAOA/G30 M-7, M-23, and M-24 to probands with schizophrenia in our family-based sample. Subsequent analysis of haplotypes made up of four DAOA/G30 markers, one marker selected from each of two linkage disequilibrium blocks that were observed in our sample as well as both ends (M-7 and M-25), were also associated with schizophrenia. Our data provide further evidence that the DAOA/G30 locus may play a role in the pathophysiology of schizophrenia. Although no direct link to genetic polymorphism in these genes and NMDA receptor function has been revealed, the present findings support previous reports implicating DAOA/G30 as susceptibility genes for schizophrenia. Further research is warranted to determine the functional variation underlying these findings and to relate this to the pathophysiology of schizophrenia.
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PMID:Association analyses of the DAOA/G30 and D-amino-acid oxidase genes in schizophrenia: further evidence for a role in schizophrenia. 1762 36

D-Serine has recently been identified as a major gliotransmitter in the mammal central nervous system (CNS). The distribution of D-serine is analogous to the N-methyl-D-aspartate (NMDA)-type glutamate receptors in the brain. D-Serine is as potent as glycine as a coagonist at the glycine-binding site of NMDA receptors. Thus, D-serine has been considered as an endogenous ligand of the NMDA receptors in the brain. D-Serine is synthesized by serine racemase (SR) from L-serine. Both D-serine and SR have been enriched to astrocytes which are the dynamic partners of neurons at synapses and participate in controlling synaptic transmission, synaptic plasticity and synaptogenesis. The present review highlights the most recent findings on the molecular mechanisms of controlling D-serine metabolism in the CNS, the physiological role of D-serine in synaptic plasticity, and the pathological relevance of D-serine to schizophrenia, excitotoxicity- and neuroinflammation-induced neuronal death as well as neuropathic pain. Finally, as we have recently established SR knockout mouse strain with pure C57BL/6 genetic background, this novel mouse model will contribute the analysis of physiological and pathophysiological role of D-serine in vivo.
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PMID:[Role of D-serine in the mammalian brain]. 1766 43

Accumulating evidence suggests that the glycine modulatory site on the NMDA receptor could be potential therapeutic target for cognitive deficits in schizophrenia. The present study was undertaken to examine the effects of the glycine transporter-1 (GlyT-1) inhibitor, (R)-(N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])sarcosine (NFPS), on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of NFPS (1.0 and 3.0 mg/kg/day) or D-serine (600 mg/kg/day). However, PCP-induced cognitive deficits were not improved by a single administration of NFPS (3.0 mg/kg). Furthermore, Western blot analysis revealed that levels of GlyT-1 in the hippocampus, but not frontal cortex, of the PCP (10 mg/kg/day for 10 days)-treated mice were significantly higher than those of saline-treated mice. An in vivo microdialysis study revealed that repeated PCP administration significantly decreased the extracellular levels of glycine in the hippocampus, but not frontal cortex, of mice. These findings suggest that repeated PCP administration increased the density of GlyT-1 in the hippocampus of mouse brain, and that the GlyT-1 inhibitor NFPS could ameliorate cognitive deficits in mice after repeated administration of PCP.
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PMID:Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the glycine transporter-1 inhibitor NFPS and D-serine. 1780 6

Compounds enhancing N-methyl-d-aspartate (NMDA) glutamate receptor function have been reported to improve cognitive deficits. Since cognitive deficits are considered to be the core symptom of schizophrenia, enhancing NMDA receptor function represents a promising approach to treating schizophrenia. In the present study, we investigated whether d-serine or a glycine transporter inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS), both of which enhance NMDA receptor function, could improve MK-801-induced cognitive deficits in rats, and compared their effects with those of the atypical antipsychotic clozapine and of the typical antipsychotic haloperidol. To assess cognitive function, we used a novel object recognition test in rats that measured spontaneous exploratory activity of a novel object when paired with a familiar object. We then evaluated the effects of the compounds on cognitive deficits induced by treatment with MK-801, the NMDA receptor antagonist. Pretreatment with clozapine (1, 5 mg/kg, i.p.) but not haloperidol (0.03, 0.1 mg/kg, i.p.) significantly improved MK-801-induced cognitive deficits. Pretreatment with D-serine at 800 mg/kg (i.p.) or NFPS (0.3, 1 mg/kg, i.p.) significantly improved MK-801-induced cognitive deficits under this test paradigm. These findings suggest that impaired preference for novel objects induced by MK-801 in the novel object recognition test could be a useful animal model for evaluating the efficacy of compounds targeting the cognitive deficits observed in schizophrenic patients. The results also suggest that enhancing NMDA receptor function is an effective way for treating the cognitive deficits associated with schizophrenia.
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PMID:D-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats. 1785 19

The N-methyl-D-aspartate receptor co-agonist d-serine is synthesized by serine racemase and degraded by D-amino acid oxidase. Both D-serine and its metabolizing enzymes are implicated in N-methyl-D-aspartate receptor hypofunction thought to occur in schizophrenia. We studied D-amino acid oxidase and serine racemase immunohistochemically in several brain regions and compared their immunoreactivity and their mRNA levels in the cerebellum and dorsolateral prefrontal cortex in schizophrenia. D-Amino acid oxidase immunoreactivity was abundant in glia, especially Bergmann glia, of the cerebellum, whereas in prefrontal cortex, hippocampus and substantia nigra, it was predominantly neuronal. Serine racemase was principally glial in all regions examined and demonstrated prominent white matter staining. In schizophrenia, D-amino acid oxidase mRNA was increased in the cerebellum, and as a trend for protein. Serine racemase was increased in schizophrenia in the dorsolateral prefrontal cortex but not in cerebellum, while serine racemase mRNA was unchanged in both regions. Administration of haloperidol to rats did not significantly affect serine racemase or D-amino acid oxidase levels. These findings establish the major cell types wherein serine racemase and D-amino acid oxidase are expressed in human brain and provide some support for aberrant D-serine metabolism in schizophrenia. However, they raise further questions as to the roles of D-amino acid oxidase and serine racemase in both physiological and pathophysiological processes in the brain.
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PMID:d-Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia. 1788 Mar 99


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