Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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

In addition to being essential supporters of neuronal function, astrocytes are now recognized as active elements in the brain. Astrocytes sense and integrate synaptic activity and, depending on intracellular Ca(2+) levels, release gliotransmitters (e.g. glutamate, d-serine and ATP) that have feedback actions on neurons. Recent experimental results have raised the possibility that quantitative variations in gliotransmission might contribute to disorders of the nervous system. Here, we discuss targeted molecular genetic approaches that have demonstrated that alterations in protein expression in astrocytes can lead to serious changes in neuronal function. We also introduce the concept of 'astrocyte activation spectrum' in which enhanced and reduced gliotransmission might contribute to epilepsy and schizophrenia, respectively. The results of future experimental tests of the astrocyte activation spectrum, which relates gliotransmission to neurological and psychiatric disorders, might point to a new therapeutic target in the brain.
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PMID:The tripartite synapse: roles for gliotransmission in health and disease. 1720 62

Prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating, is decreased in schizophrenia. The validity of a glutamatergic, N-methyl-d-aspartate receptor (NMDAR)-mediated model of PPI disruption is presently equivocal. The NMDAR antagonist ketamine disrupts PPI in rodents, but may increase PPI in healthy volunteers. Glycine (GLY), which acts as an obligatory co-agonist at the NMDAR-GLY site, induces PPI deficits in rats although, consistent with the hypo-NMDAR hypothesis, improves negative and cognitive symptoms in schizophrenia patients. We assessed the hypothesis that GLY serum levels may affect PPI parameters in schizophrenia. Forty-five chronically ill medicated schizophrenia patients and 37 matched healthy comparison subjects were tested for PPI of the eyeblink component of the startle reflex measured by electromyogram recording. Patients' demographic variables, symptom severity scores and GLY, serine and glutamate serum levels were obtained. Patients showed deficient PPI in blocks two and three of the PPI session and differed from controls in terms of change of degree of PPI as a function of the prepulse to eliciting stimulus interval. GLY levels correlated negatively with PPI parameters, such that patients with the highest GLY levels showed decreased PPI (rs=-0.4, p=0.03). These preliminary findings indirectly support previous observations on ketamine effects upon PPI in humans and suggest a dissociation of symptomatology and PPI changes as function of NMDAR modulation in schizophrenia.
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PMID:High glycine levels are associated with prepulse inhibition deficits in chronic schizophrenia patients. 1727 36

Prolyl oligopeptidase is a cytosolic serine peptidase that hydrolyzes proline-containing peptides at the carboxy terminus. This peptidase has been associated with schizophrenia, bipolar affective disorder, and related neuropsychiatric disorders, and therefore may have important clinical implications. Among the strategies used to find novel prolyl oligopeptidase inhibitors, traditional Chinese medicinal plants provide a rich source of unexplored compounds. We used (19)F NMR spectroscopy to search for new prolyl oligopeptidase inhibitors in a library of traditional Chinese medicine plant extracts. Several extracts were identified as powerful inhibitors of this peptidase. The alkaloid berberine was the prolyl oligopeptidase inhibitory molecule isolated from Rhizoma coptidis extract. Berberine inhibited prolyl oligopeptidase in a dose-dependent manner. As berberine is a natural compound that has been safely administered to humans, it opens up new perspectives for the treatment of neuropsychiatric diseases. The results described herein suggest that the initiation of clinical trials in patients with schizophrenia, bipolar affective disorder, or related diseases in which cognitive capabilities are affected should be undertaken with either the extract or pure BBR.
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PMID:The natural product berberine is a human prolyl oligopeptidase inhibitor. 1729 71

Disturbance in glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia. Since glutamate receptor interacting protein 1 (GRIP1), a modular protein that enables anchoring of AMPA receptors via its PDZ (postsynaptic density-95/discs large/zona occludens-1) domain and modulates d-serine release, plays an important role in glutamatergic function, this study tests the hypothesis that GRIP1 genetic variants confer susceptibility to schizophrenia. This study investigated whether GRIP1 genetic polymorphisms (rs1038923 and rs4913301) cause a predisposal to schizophrenia. Two GRIP1 polymorphisms were studied in a sample population of 252 people with schizophrenia and 207 normal controls. Significant linkage disequilibrium was obtained between the two polymorphisms. Results demonstrated that neither single marker nor haplotype analysis revealed an association between variants at the GRIP1 locus and schizophrenia, suggesting that it is unlikely that the GRIP1 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia. However, association between schizophrenia and other polymorphisms in the GRIP1 gene cannot be totally ruled out as the whole gene was not covered by the two polymorphisms studied.
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PMID:No association of GRIP1 gene polymorphisms with schizophrenia in Chinese population. 1730 96

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

Schizophrenia is a serious mental disorder that affects up to 1% of the population worldwide. As of yet, neurochemical mechanisms underlying schizophrenia remain unknown. To date, the most widely considered neurochemical hypothesis of schizophrenia is the dopamine hypothesis, which postulates that symptoms of schizophrenia may result from excess dopaminergic neurotransmission particularly in striatal brain regions, along with dopaminergic deficits in prefrontal brain regions. Alternative neurochemical models of schizophrenia, however, have been proposed involving glutamatergic mechanisms in general and N-methyl-D-aspartate (NMDA) receptors in particular. A potential role for glutamatergic mechanisms in schizophrenia was first proposed approximately 15 years ago based on the observation that the psychotomimetic agents phencyclidine (PCP) and ketamine induce psychotic symptoms and neurocognitive disturbances similar to those of schizophrenia by blocking neurotransmission at NMDA-type glutamate receptors. Since that time, significant additional evidence has accumulated supporting a role for NMDA hypofunction in the pathophysiology of schizophrenia. Clinical challenge studies with PCP and ketamine have confirmed the close resemblance between NMDA antagonist-induced symptoms and neurocognitive deficits and those observed in schizophrenia, and suggest that NMDA dysfunction may lead to secondary dopaminergic dysregulation in striatal and prefrontal brain regions. As compared to dopaminergic agents, NMDA antagonists induce negative and cognitive symptoms of schizophrenia, as well as positive symptoms. Treatment studies with NMDA modulators, such as glycine, d-serine, and glycine transport inhibitors (GTIs), have yielded encouraging findings, although results remain controversial. Finally, genetic linkage and in vivo neurochemical studies in schizophrenia highlight potential etiological mechanisms giving rise to glutamatergic/NMDA dysfunction in schizophrenia.
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PMID:Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions. 1734 58

D(3) dopamine receptor (D(3)R) is expressed mainly in parts of the brain that control the emotional behaviors. It is believed that the improper regulation of D(3)R is involved in the etiology of schizophrenia. Desensitization of D(3)R is weakly associated with G protein-coupled receptor kinase (GRK)/beta-arrestin-directed internalization. This suggests that there might be an alternative pathway that regulates D(3)R signaling. This report shows that D(3)R undergoes robust protein kinase C (PKC)-dependent sequestration that is accompanied by receptor phosphorylation and the desensitization of signaling. PKC-dependent D(3)R sequestration, which was enhanced by PKC-beta or -delta, was dynamin dependent but independent of GRK, beta-arrestin, or caveolin 1. Site-directed mutagenesis of all possible phosphorylation sites within the intracellular loops of D(3)R identified serine residues at positions 229 and 257 as the critical amino acids responsible for phorbol-12-myristate-13-acetate (PMA)-induced D(3)R phosphorylation, sequestration, and desensitization. In addition, the LxxY endocytosis motif, which is located between residues 252 and 255, was found to play accommodating roles for PMA-induced D(3)R sequestration. A continuous interaction with the actin-binding protein 280 (filamin A), which was previously known to interact with D(3)R, is required for PMA-induced D(3)R sequestration. In conclusion, the PKC-dependent but GRK-/beta-arrestin-independent phosphorylation of D(3)R is the main pathway responsible for the sequestration and desensitization of D(3)R. Filamin A is essential for both the efficient signaling and sequestration of D(3)R.
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PMID:Roles of protein kinase C and actin-binding protein 280 in the regulation of intracellular trafficking of dopamine D3 receptor. 1753 8

Glycogen synthase kinase 3 (GSK3) was recently suggested to be a potential target of psychotropics used in psychiatric illnesses such as schizophrenia and bipolar disorder. Relevant studies have found that antipsychotic drugs regulate GSK3 activity via an increase in either inhibitory serine phosphorylation or amount of GSK3 after acute or subchronic treatment. Recent evidence shows that GSK3 is regulated by dopaminergic or serotonergic systems implicated in the pathophysiology and treatment mechanisms of schizophrenia and bipolar disorder. Therefore, antipsychotics may regulate GSK3 via antagonizing dopaminergic or serotonergic activity. However, the signaling pathway that is involved in GSK3 regulation by dopaminergic or serotonergic systems has not been well established. Haloperidol is a typical antipsychotic with potent dopamine D(2) receptor antagonism. Clozapine is an atypical antipsychotic with potent serotonin 5HT(2) receptor antagonism. We injected rats with haloperidol or clozapine and examined the phosphorylation and amount of GSK3alpha/beta and its well-known upstream regulators Akt and Dvl in the rat frontal cortex by Western blotting. Both haloperidol and clozapine induced Ser21/9 phosphorylation of GSK3GSK3alpha/beta. Haloperidol increased the Ser473 phosphorylation of Akt transiently, whereas clozapine maintained the increase for 1 h. Haloperidol did not affect the phosphorylation and amount of Dvl, whereas clozapine increased both phosphorylation and the amount of Dvl. Our results suggest that GSK3 activity may be regulated by both typical and atypical antipsychotics and that Akt or Dvl, depending on the D(2)- or 5HT(2)- receptor antagonism properties of typical and atypical antipsychotics, mediate the regulation differently.
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PMID:Haloperidol and clozapine differentially regulate signals upstream of glycogen synthase kinase 3 in the rat frontal cortex. 1760 89

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


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