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)

The mRNAs encoding kainic acid (KA) preferring glutamate receptor subunits (GluR5-7, KA1 and KA2) are differentially expressed in rat brain. We have used regional and cellular in situ hybridization histochemistry with subunit-specific 35S-labelled oligodeoxyribonucleotides to examine these mRNAs in adult human hippocampus, neocortex and cerebellum. GluR5 mRNA was detected only in Purkinje cells and a few scattered hippocampal neurons. GluR6 mRNA was relatively abundant in all areas, notably in dentate gyrus, pyramidal neurons of CA3, and cerebellar granule cells, as well as being present in superficial and deep laminae of the neocortex. Moderate signal for GluR7 mRNA was seen in deep laminae of the neocortex with a weak signal in the dentate gyrus; in dipped sections GluR7 mRNA was also apparent over some pyramidal and non-pyramidal cells in hippocampus and over putative cerebellar stellate/basket cells. KA1 mRNA was detected in the dentate gyrus but not reliably elsewhere. The expression profile and abundance of KA2 mRNA was similar to that of GluR6 mRNA. For all five transcripts, concurrent hybridization of rat brain sections produced the anticipated distribution of signal. The data indicate that the regional and cellular distribution of KA receptor subunit mRNAs in human hippocampus, neocortex and cerebellum largely parallels that in the corresponding areas of rat brain, albeit at lower levels, especially with regard to GluR5 and KA1 transcripts. In schizophrenia there is a partial loss of hippocampal non-NMDA receptors, but there are no data concerning KA receptor subunit expression. KA2 and GluR6 mRNAs were sufficiently abundant for a comparison in the left and right hippocampus between 11 schizophrenics and 13 controls. Using film autoradiography, both mRNAs were significantly reduced in the schizophrenics, having controlled for the effects of brain pH, post mortem interval and age. GluR6 mRNA was also quantitated in cerebellum, wherein no differences were found between cases and controls. In conjunction with earlier findings of reduced hippocampal GluR1 and GluR2 expression and a loss of [3H]KA binding sites, these data show that schizophrenia is associated with impaired expression of both AMPA- and KA-preferring ionotropic glutamate receptors. These deficits are likely to contribute to the glutamatergic component of the disease pathophysiology.
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PMID:Distribution of kainate receptor subunit mRNAs in human hippocampus, neocortex and cerebellum, and bilateral reduction of hippocampal GluR6 and KA2 transcripts in schizophrenia. 909 8

Dopamine-glutamate interactions within discrete neural circuits are increasingly recognized as potential substrates for dysregulation in schizophrenia, and as a result, potential targets for pharmacological intervention in this illness. We examined the regulation, by haloperidol (2 mg kg-1 day-1) and clozapine (20 mg kg-1 day-1), of the mRNAs encoding the four AMPA receptor subunits (gluR1-gluR4), three low-affinity kainate receptor subunits (gluR5-gluR7), and two high-affinity kainate subunits (KA1 and KA2) in the rat hippocampal formation and associated entorhinal cortex. A complex and differential pattern of AMPA and kainate subunit mRNA regulation by clozapine and haloperidol was observed in this study. Both drugs caused significant alterations of most of these mRNAs, but in a heterogeneous and region-specific fashion. These data suggest that these antipsychotic drugs alter the expression of the genes encoding the subunits that express ionotropic glutamate receptors. Given the importance of glutamatergic mechanisms and the hippocampal formation in schizophrenia, these data suggest a potential substrate for neurotransmitter dysregulation in this illness, as well as a potential target for therapeutic intervention.
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PMID:Differential regulation of hippocampal AMPA and kainate receptor subunit expression by haloperidol and clozapine. 911 9

Dopamine is the neurotransmitter most often implicated in the pathogenesis of schizophrenia. However, glutamatergic antagonists can cause psychotic symptoms in otherwise normal humans, and exacerbate these symptoms in schizophrenics. These findings have led to a model of dopamine-glutamate interactions in limbic cortex and striatum as a potential substrate for symptom production in schizophrenia. From this model, we might expect that cortical and striatal expression of non-NMDA ionotropic glutamate receptors would be differentially regulated by antipsychotic treatment. To begin to address this question, we examined the regulation of mRNA levels of the AMPA (gluR1-gluR4), low affinity kainate (gluR5-gluR7), and high affinity kainate (KA1-KA2) receptor subunits by clozapine (20 mg/kg/day) and haloperidol (2 mg/kg/day) treatment for 2 weeks. Both clozapine and haloperidol caused region-specific alterations in the mRNA levels of these subunits, but there was no differential regulation in the cortex vs. the striatum. Haloperidol caused a decrease in gluR2 and gluR4 mRNA levels in both cortex and striatum and an increase in KA2 mRNA levels in the striatum only. However, clozapine treatment caused an increase in gluR7 mRNA expression, and a decrease in gluR3 mRNA expression, in both cortex and striatum while causing an increase in KA2 mRNA levels, and a decrease in gluR4 mRNA levels, in the striatum only. These dissimilarities may represent an interesting mechanism for some of the differential therapeutic or toxic effects of clozapine and haloperidol, and also may be relevant to our understanding of dopamine-glutamate interactions in schizophrenia.
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PMID:Clozapine and haloperidol differentially affect AMPA and kainate receptor subunit mRNA levels in rat cortex and striatum. 922 32

Schizophrenics exhibit abnormalities in many memory-associated functions mediated by the frontal cortex. Glutamate receptors play key roles in learning and memory. Hence, abnormalities in glutamate receptors within the frontal cortex may be associated with schizophrenia. In addition, emerging evidence indicates that glutamate receptors may be involved in the actions of antipsychotic drugs. To test these hypotheses, we measured mRNAs encoding the NMDAR1, GluR1, GluR7, and KA1 subunits of glutamate receptor in the left superior frontal gyrus from 21 elderly schizophrenics with varying histories of antipsychotic drug treatment and nine normal drug-free elderly controls. There were significant negative correlations between NMDAR1, GluR1, GluR7, and KA1 mRNA levels and time without neuroleptic medication before death in schizophrenics, indicating that levels of the glutamate receptor mRNAs decline rapidly after drug withdrawal. Further analysis revealed that in "neuroleptic-free" (>6 months) schizophrenics, levels of NMDAR1, GluR1, GluR7, and KA1 mRNAs were significantly lower than in controls. By contrast, in schizophrenics who were receiving neuroleptics until death, levels of NMDAR1, GluR1, GluR7, and KA1 mRNAs did not differ significantly from controls. These findings indicate that decreased levels of NMDAR1, GluR1, GluR7, and KA1 mRNAs may be present in the frontal cortex of some schizophrenics and that typical neuroleptics may reversibly increase levels of these mRNAs.
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PMID:Expression of NMDAR1, GluR1, GluR7, and KA1 glutamate receptor mRNAs is decreased in frontal cortex of "neuroleptic-free" schizophrenics: evidence on reversible up-regulation by typical neuroleptics. 983 44

Glutamate receptor function has been hypothesized as an important factor in both the aetiology and treatment of schizophrenia. We have used a multiprobe oligonucleotide solution hybridization (MOSH) technique to examine the regulation of gene expression of the GluR1-7, KA1, and KA2 glutamate receptor subunits in the left rat brain following treatment with the optical isomers of flupenthixol at a dose of 0.2 mg kg-1 day-1 over a period of 4, 12, 24 weeks in order to understand how specific glutamate receptor genes are involved in the treatment of schizophrenia. The GluR2/3 and GluR6/7 subunit immunoreactivity in the right brain following 4 and 24 weeks of drug treatment was also examined by Western blotting. Neither trans- nor cis-flupenthixol was found to alter the gene expression of any of the 9 non-NMDA glutamate receptor subunits. On the other hand, we found a nearly two-fold increase in gene expression of the D2 dopamine receptor in specific brain regions. These results suggest that non-NMDA types of glutamate receptor subunits, in contrast to NMDA receptors, are less likely to have a role in the action of antipsychotic drugs.
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PMID:D2 dopamine receptor but not AMPA and kainate glutamate receptor genes show altered expression in response to long term treatment with trans- and cis-flupenthixol in the rat brain. 1032 Jul 79

We have created a transgenic mouse with a hypomorphic allele of the vesicular monoamine transporter 2 (Vmat2) gene by gene targeting. These mice (KA1) have profound changes in monoamine metabolism and function and survive into adulthood. Specifically, these animals express very low levels of VMAT2, an endogenous protein which sequesters monoamines intracellularly into vesicles, a process that, in addition to being important in normal transmission, may also act to keep intracellular levels of the monoamine neurotransmitters below potentially toxic thresholds. Homozygous mice show large reductions in brain tissue monoamines, motor impairments, enhanced sensitivity to dopamine agonism, and changes in the chemical neuroanatomy of the striatum that are consistent with alterations in the balance of the striatonigral (direct) and striatopallidal (indirect) pathways. The VMAT2-deficient KA1 mice are also more vulnerable to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in terms of nigral dopamine cell death. We suggest that the mice may be of value in examining, long term, the insidious damaging consequences of abnormal intracellular handling of monoamines. On the basis of our current findings, the mice are likely to prove of immediate interest to aspects of the symptomatology of parkinsonism. They may also, however, be of use in probing other aspects of monoaminergic function and dysfunction in the brain, the latter making important contributions to the pathogenesis of schizophrenia and addiction.
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PMID:Mice with very low expression of the vesicular monoamine transporter 2 gene survive into adulthood: potential mouse model for parkinsonism. 1146 16

Post-mortem studies have yet to produce consistent findings on cortical glutamatergic markers in schizophrenia; therefore, it is not possible to fully understand the role of abnormal glutamatergic function in the pathology of the disorder. To better understand the changes in cortical glutamatergic markers in schizophrenia, we measured the binding of radioligands to the ionotropic glutamate receptors (N-methyl D-aspartate, [3H]CGP39653, [3H]MK-801), amino-3-hydroxy-5-methyl-4-isoxazole ([3H]AMPA), kainate ([3H]kainate), and the high-affinity glutamate uptake site ([3H]aspartate) using in situ radioligand binding with autoradiography and levels of mRNA for kainate receptors using in situ hybridization in the dorsolateral prefrontal cortex from 20 subjects with schizophrenia and 20 controls matched for age and sex. Levels of [3H]kainate binding were significantly decreased in cortical laminae I-II (p = 0.01), III-IV (p < 0.05), and V-VI (p < 0.01) from subjects with schizophrenia. By contrast, levels of [3H]MK-801, [3H]AMPA, [3H]aspartate, or [3H]CGP39653 binding did not differ between the diagnostic cohorts. Levels of mRNA for the GluR5 subunit were decreased overall (p < 0.05), with no changes in levels of mRNA for GluR6, GluR7, KA1, or KA2 in tissue from subjects with schizophrenia. These data indicate that the decreased number of kainate receptors in the dorsolateral prefrontal cortex in schizophrenia may result, in part, from reduced expression of the GluR5 receptor subunits.
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PMID:Cortical glutamatergic markers in schizophrenia. 1648 93

In the search for the biological causes of schizophrenia and bipolar disorder, glutamate neurotransmission has emerged as one of a number of candidate processes and pathways where underlying gene deficits may be present. The analysis of chromosomal rearrangements in individuals diagnosed with neuropsychiatric disorders is an established route to candidate gene identification in both Mendelian and complex disorders. Here we describe a set of genes disrupted by, or proximal to, chromosomal breakpoints (2p12, 2q31.3, 2q21.2, 11q23.3 and 11q24.2) in a patient where chronic schizophrenia coexists with mild learning disability (US: mental retardation). Of these disrupted genes, the most promising candidate is a member of the kainate-type ionotropic glutamate receptor family, GRIK4 (KA1). A subsequent systematic case-control association study on GRIK4 assessed its contribution to psychiatric illness in the karyotypically normal population. This identified two discrete regions of disease risk within the GRIK4 locus: three single single nucleotide polymorphism (SNP) markers with a corresponding underlying haplotype associated with susceptibility to schizophrenia (P=0.0005, odds ratio (OR) of 1.453, 95% CI 1.182-1.787) and two single SNP markers and a haplotype associated with a protective effect against bipolar disorder (P=0.0002, OR of 0.624, 95% CI 0.485-0.802). After permutation analysis to correct for multiple testing, schizophrenia and bipolar disorder haplotypes remained significant (P=0.0430, s.e. 0.0064 and P=0.0190, s.e. 0.0043, respectively). We propose that these convergent cytogenetic and genetic findings provide molecular evidence for common aetiologies for different psychiatric conditions and further support the 'glutamate hypothesis' of psychotic illness.
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PMID:Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder. 1681 33

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

Underactivity of the glutamatergic system is an attractive model for the pathophysiology of several major mental illnesses. We previously described a chromosome abnormality disrupting the kainate class ionotropic glutamate receptor gene, GRIK4/KA1, in an individual with schizophrenia and learning disability (mental retardation). We also demonstrated in a case-control study that two physically separated haplotypes within this gene were significantly associated with increased risk of schizophrenia and decreased risk of bipolar disorder, respectively. The latter protective haplotype was located at the 3' end of the gene. We now report the identification from carriers of the protective haplotype of a deletion variant within the 3' untranslated region of the gene. The deletion allele also was found to be negatively associated with bipolar disorder in both initial (P = 0.00000019) and replication (P = 0.0107) case-control studies. Expression studies indicated that deletion-carrying mRNA transcripts were relatively more abundant. We postulate that this may be a direct consequence of the differences in the RNA secondary structures predicted for the insertion and deletion alleles. These data suggest a mechanism whereby the genetic protective effect is mediated through increased kainate receptor expression.
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PMID:A common variant in the 3'UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder. 1882 90


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