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)

NMDA receptor antagonists can induce a schizophrenia-like psychosis, but the role of NMDA receptors in the pathophysiology of schizophrenia remains unclear. Expression patterns of mRNAs for five NMDA receptor subunits (NR1/NR2A-D) were determined by in situ hybridization in prefrontal, parieto-temporal, and cerebellar cortex of brains from schizophrenics and from neuroleptic-treated and nonmedicated controls. In the cerebral cortex of both schizophrenics and controls, mRNAs for NR1, NR2A, NR2B, and NR2D subunits were preferentially expressed in layers II/III, Va, and VIa, with much higher levels in the prefrontal than in the parieto-temporal cortex. Levels of mRNA for the NR2C subunit were very low overall. By contrast, the cerebellar cortex of both schizophrenics and controls contained very high levels of NR2C subunit mRNA, whereas levels for the other subunit mRNAs were very low, except NR1, for which levels were moderate. Significant alterations in the schizophrenic cohort were confined to the prefrontal cortex. Here there was a shift in the relative proportions of mRNAs for the NR2 subunit family, with a 53% relative increase in expression of the NR2D subunit mRNA. No comparable changes were found in neuroleptic-treated or untreated controls. These findings indicate regional heterogeneity of NMDA receptor subunit expression in human cerebral and cerebellar cortex. In schizophrenics, the alterations in expression of NR2 subunit mRNA in prefrontal cortex are potential indicators of deficits in NMDA receptor-mediated neurotransmission accompanying functional hypoactivity of the frontal lobes.
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PMID:Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics. 861 85

Both direct and indirect evidence implicate excitatory amino acid neurotransmission in the aetiology of schizophrenia. The data are particularly suggestive for N-methyl-D-aspartate (NMDA) neurotransmission. Four of the six genes coding for subunits of the neural NMDA receptor have been mapped. We have studied segregation and allele sharing of markers in these four regions in a sample of southern African Bantu-speaking families multiply affected with DSM-III-R schizophrenia. This population was chosen because anthropological and linguistic data suggest that it has diverged from a small initial population within the past 1000 years, making shared genetic aetiology more likely. We find positive LOD score maxima of 0.876 at a marker D9S1838 on chromosome 9q34.3 near the NMDAR1 central subunit gene, 0.758 at marker D17S784 on chromosome 17q25 near the NMDAR2C potentiating subunit gene, and 0.453 at marker D12S77 near the NMDAR2B gene on chromosome 12p12 when analysing affected samples only. Only the region of NMDAR2A, on chromosome 16p13, can be excluded in this population. There is evidence of increased allele sharing on chromosomes 9p34.3 and 17q25 using APM. Multipoint allele-sharing analysis using GENEHUNTER does not reject possible effects on chromosome 9q34.3, but does not support any involvement of chromosome 17q25. We propose that the NMDA receptor may be involved in the genetic predisposition to schizophrenia in this population through covariation in several of the subunits, which is consistent with the genetic models of the inheritance of the disease.
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PMID:A linkage study of the N-methyl-D-aspartate receptor subunit gene loci and schizophrenia in southern African Bantu-speaking families. 928 63

Schizophrenia has been associated with dysfunction of glutamatergic neurotransmission. Synaptic glutamate activates pre- and postsynaptic ionotropic NMDA, AMPA, and kainate and metabotropic receptors, is removed from the synapse via five cell surface-expressed transporters, and is packaged for release by three vesicular transporters. In addition, there is a family of intracellular molecules enriched in the postsynaptic density (PSD) that target glutamate receptors to the synaptic membrane, modulate receptor activity, and coordinate glutamate receptor-related signal transduction. Each family of PSD proteins is selective for a given glutamate receptor subtype, the most well characterized being the NMDA receptor binding proteins PSD93, PSD95, NF-L, and SAP102. Besides binding glutamate receptors, many of these proteins also interact with cell surface proteins like cell adhesion molecules, ion channels, cytoskeletal elements, and signal transduction molecules. Given the complexity of the glutamate neurotransmitter system, there are many locations where disruption of normal signaling could occur and give rise to abnormal glutamatergic neurotransmission in schizophrenia. Using multiple cohorts of postmortem tissue, we have examined these synaptic molecules in schizophrenic thalamus. The expression of NR1 and NR2C subunit transcripts is decreased in the thalamus in schizophrenia. Interestingly, three intracellular PSD molecules that link the NMDA receptor to signal transduction pathways are also abnormally expressed. Additionally, several of the cell surface and vesicular transporters are abnormal in the schizophrenic thalamus. While occasional findings of abnormal receptor expression are made, the most dramatic and consistent alterations that we have found in the thalamus in schizophrenia involve the family of intracellular signaling/scaffolding molecules. We propose that schizophrenia has a glutamatergic component that involves alterations in the intracellular machinery that is coupled to glutamate receptors, in addition to abnormalities of the receptors themselves. Our data suggest that schizophrenia is associated with abnormal glutamate receptor-related intracellular signaling in the thalamus, and point to novel targets for innovative drug discovery.
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PMID:Molecular abnormalities of the glutamate synapse in the thalamus in schizophrenia. 1468 36

The hypothesis of N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia was initially based on observations that blockade of the NMDA subtype of glutamate receptor by noncompetitive antagonists, such as phencyclidine and ketamine, can lead to clinical symptoms similar to those present in schizophrenia. Recently, glutamate has also been implicated in the pathophysiology of the mood disorders. As impaired NMDA receptor activity may be the result of a primary defect in the NMDA receptors themselves, or secondary to dysfunction in the protein complexes that mediate their signaling, we measured expression of both NMDA subunits and associated postsynaptic density (PSD) proteins (PSD95, neurofilament-light (NF-L), and SAP102) transcripts in the dorsolateral prefrontal cortex in subjects with schizophrenia, bipolar disorder, major depression, and a comparison group using tissue from the Stanley Foundation Neuropathology Consortium. We found decreased NR1 expression in all three illnesses, decreased NR2A in schizophrenia and major depression, and decreased NR2C in schizophrenia. We found no changes of NR2B or NR2D. Receptor autoradiography revealed no alterations in receptor binding in any of the illnesses, indicating no change in total receptor number, but taken with the subunit data suggests abnormal receptor stoichiometry. In the same subjects, PSD95 was unchanged in all three illnesses, while reduced NF-L expression was found in schizophrenia, especially in large cells of layer V. SAP102 expression was reduced in bipolar disorder restricted to small cells of layer II and large cells of layer III in bipolar disorder. These alterations likely reflect altered signaling cascades associated with glutamate-mediated neurotransmission within specific cortical circuits in these psychiatric illnesses.
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PMID:Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder. 1803 38

Abnormalities in glutamate neurotransmission are thought to be among the major contributing factors to the pathophysiology of schizophrenia. Although schizophrenia has been regarded mostly as a disorder of higher cortical function, the cortex and thalamus work as a functional unit. Existing data regarding alterations of glutamate receptor subunit expression in the thalamus in schizophrenia remain equivocal. This postmortem study examined mRNA expression of ionotropic glutamate receptor (iGluR) subunits and PSD95 in 5 precisely defined and dissected thalamic subdivisions (medial and lateral sectors of the mediodorsal nucleus; and the ventral lateral posterior, ventral posterior, and centromedian nuclei) of persons with schizophrenia and matched controls using quantitative PCR with normalization to multiple endogenous controls. Among 15 genes examined (NR1 and NR2A-D subunits of the NMDA receptor; GluR1-4 subunits of the AMPA receptor; GluR5-7 and KA1-2 subunits of the kainate receptor; PSD95), all but two (GluR4 and KA1) were expressed at quantifiable levels. Differences in iGluR gene expression were seen between different thalamic nuclei but not between diagnostic groups. The relative abundance of transcripts was: NR1>>NR2A>NR2B>NR2D>NR2C for NMDA, GluR2>GluR1>GluR3 for AMPA, and KA2>GluR5>GluR7>GluR6 for kainate receptors. The expression of PSD95 correlated with the expression of NR1, NR2A, NR2B, NR2D and GluR6 in all nuclei. These results provide detailed and quantitative information on iGluR subunit expression in multiple nuclei of the human thalamus but suggest that alterations in their expression are not a prominent feature of schizophrenia.
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PMID:Ionotropic glutamate receptor mRNA expression in the human thalamus: absence of change in schizophrenia. 1846 8

N-methyl-d-aspartate (NMDA) receptors (NMDARs) are a major class of excitatory neurotransmitter receptors in the central nervous system. They form glutamate-gated ion channels that are highly permeable to calcium and mediate activity-dependent synaptic plasticity. NMDAR dysfunction is implicated in multiple brain disorders, including stroke, chronic pain and schizophrenia. NMDARs exist as multiple subtypes with distinct pharmacological and biophysical properties that are largely determined by the type of NR2 subunit (NR2A to NR2D) incorporated in the heteromeric NR1/NR2 complex. A fundamental difference between NMDAR subtypes is their channel maximal open probability (P(o)), which spans a 50-fold range from about 0.5 for NR2A-containing receptors to about 0.01 for receptors containing NR2C and NR2D; NR2B-containing receptors have an intermediate value (about 0.1). These differences in P(o) confer unique charge transfer capacities and signalling properties on each receptor subtype. The molecular basis for this profound difference in activity between NMDAR subtypes is unknown. Here we show that the subunit-specific gating of NMDARs is controlled by the region formed by the NR2 amino-terminal domain (NTD), an extracellular clamshell-like domain previously shown to bind allosteric inhibitors, and the short linker connecting the NTD to the agonist-binding domain (ABD). The subtype specificity of NMDAR P(o) largely reflects differences in the spontaneous (ligand-independent) equilibrium between open-cleft and closed-cleft conformations of the NR2-NTD. This NTD-driven gating control also affects pharmacological properties by setting the sensitivity to the endogenous inhibitors zinc and protons. Our results provide a proof of concept for a drug-based bidirectional control of NMDAR activity by using molecules acting either as NR2-NTD 'closers' or 'openers' promoting receptor inhibition or potentiation, respectively.
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PMID:Mechanism of differential control of NMDA receptor activity by NR2 subunits. 1940 60

A hypofunction of the N-methyl-D-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. Compelling evidence of altered NMDA receptor subunit expression in the schizophrenic brain has not, however, so far emerged. Rats reared in isolation exhibit several characteristics, including disturbed sensory gating, which resemble those seen in schizophrenia. To explore the possibility that NMDA receptor dysfunction may contribute to the behavioral and neurochemical consequences of rearing rats in isolation, we compared NMDA receptor subunit expression in brains of rats which were housed in isolation and which displayed a deficit in prepulse inhibition of the acoustic startle response with that of socially housed controls. An initial microarray analysis revealed a 1.26-fold increase in NR2A transcript in the prefrontal cortex, but not in the nucleus accumbens, of rats reared in isolation compared with those housed socially. In contrast, NR1, NR2B, NR2C, NR2D, NR3A, and NR3B subunit expression was unchanged in either brain area. In a second cohort of animals, in situ hybridization revealed increased NR2A mRNA expression in the medial prefrontal cortex, an observation that was substantiated by increased [(3)H]CGP39653 binding suggesting that NR2A receptor subunit protein expression was also elevated in the medial prefrontal cortex of the same animals. No changes in expression of NR1 or NR2B subunits were observed at both mRNA and protein level. Altered NR2A subunit expression in the medial prefrontal cortex of rats reared in isolation suggests that NMDA receptor dysfunction may contribute to the underlying pathophysiology of this preclinical model of aspects of schizophrenia.
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PMID:Increased expression of the NR2A NMDA receptor subunit in the prefrontal cortex of rats reared in isolation. 1953 26

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

Injection of NMDAR antagonist into the thalamus can produce delta frequency EEG oscillations in the thalamocortical system. It is surprising that an antagonist of an excitatory neurotransmitter should trigger such activity, and the mechanism is unknown. One hypothesis is that the antagonist blocks excitation of GABAergic cells, thus producing disinhibition. To test this hypothesis, we investigated the effect of NMDAR antagonist (APV) on cells of the nucleus reticularis (nRT) in rat brain slices, a thalamic nucleus that can serve as a pacemaker for thalamocortical delta oscillations and that is composed entirely of GABAergic neurons. We found, unexpectedly, that nRT cells are hyperpolarized by APV. This occurs because these cells have an unusual form of NMDAR (probably NR2C) that contributes inward current at resting potential in response to ambient glutamate. The hyperpolarization produced by APV is sufficient to deinactivate T-type calcium channels, and these trigger rhythmic bursting at delta frequency. The APV-induced delta frequency bursting is abolished by dopamine D2 receptor antagonist, indicating that dopamine and NMDAR antagonist work synergistically to stimulate delta frequency bursting. Our results have significant implications concerning the electrophysiological basis of schizophrenia and bring together the NMDAR hypofunction, dopamine, and GABA theories of the disease. Our results suggest that NMDAR hypofunction and dopamine work synergistically on the GABAergic cells of the nRT to generate the delta frequency EEG oscillations, a thalamocortical dysrhythmia (TCD) in the awake state that is an established abnormality in schizophrenia.
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PMID:Inhibition of NMDARs in the Nucleus Reticularis of the Thalamus Produces Delta Frequency Bursting. 2005 28

Virus mediated RNA-interference (RNAi) is a powerful approach to study genes in vivo. Here we report a method using lentivirus-delivered RNAi to knockdown the glial enzyme, D-amino acid oxidase (DAO), in the mouse cerebellum. After initial characterisation in vitro, we achieved a 40-50% reduction of DAO mRNA in the cerebellum 7 and 28 days after a single injection of lentivirus encoding a DAO-specific, short-hairpin RNA. Injections also decreased DAO immunoreactivity (-33%). The major substrate for DAO is D-serine, an N-methyl-D-aspartate receptor (NMDAR) co-agonist. Thus, we also measured whether DAO knockdown impacted on d-serine, or expression of NMDAR subunits, and found that DAO RNAi led to increased cerebellar D-serine levels (+77%), and decreased NMDAR subunit NR2A mRNA (-22%), but did not affect NR1 or NR2C mRNAs. These data demonstrate the utility of lentiviruses to deliver RNAi to glial cells within the cerebellum, and confirm the role of DAO in D-serine metabolism. They also provide a tool to investigate DAO, an enzyme currently of considerable interest in the pathophysiology and therapy of schizophrenia.
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PMID:D-amino acid oxidase knockdown in the mouse cerebellum reduces NR2A mRNA. 2082 14


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