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

1. Phencyclidine (PCP), a non-competitive NMDA-receptor antagonist, is able to induce schizophrenia-like symptoms in animals and in humans. It is known that schizophrenic patients have deficits in memory processes. 2. Therefore, it was investigated whether subchronic pulsatile or continuous application of 5.0 mg kg(-1) PCP over 5 days induce short-term memory deficits in holeboard learning and the action of two different neuroleptics on this behavioural test. 3. First, an impairment in the holeboard task was described when the animals were tested 24 h after the last application but not after 15 min or 1 h after the last injection. Secondly, the influence of haloperidol and risperidone on the PCP-induced short-term memory changes was tested. 4. The combined application of PCP and risperidone led to a complete antagonism of the short-term deficits, but the combined treatment with haloperidol was accompanied by a partial abolishment of the PCP-induced deficits. 5. PCP led to an upregulation of the glutamate binding sites in striatum and nucleus accumbens whereas the D(2) binding sites were reduced in striatum. The D(1) binding sites seem to be unchanged. The receptor protein expression of glutamate receptors mGluR1, GluR2, GluR5/7 and NMDAR1 were not modified in response to PCP treatment. 6. The determination of a subpopulation of GABAergic interneurons shows a decrease of the cells within the CA3 of the hippocampal formation. 7. These findings indicate that PCP induced impairments in short term memory can be detected by holeboard learning and may provide an interesting tool for the search of new neuroleptics.
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PMID:Neuroleptics ameliorate phencyclidine-induced impairments of short-term memory. 1078 Sep 95

The glutamatergic dysfunction hypothesis suggests genes involved in glutamatergic transmission as candidates for schizophrenia susceptibility genes. We screened single nucleotide polymorphisms (SNPs) in the entire coding sequence of the GluR5 kainate receptor gene, GRIK1, by polymerase chain reaction-single strand conformation polymorphism and direct sequencing. We identified six SNPs including three known ones, 522A/C (174T, synonymous), 1173C/T (391D, synonymous), and 2705C/T (902L/S), as well as three novel ones, 995C/T (332A/V), 2400C/T (800L, synonymous), and 2585A/G (862R/Q). We genotyped Japanese samples of schizophrenia (n = 193-203) and healthy controls (n = 199-215) for three SNPs those were commonly observed in our samples, 522A/C, 1173C/T, and 2705C/T. We observed no significant associations of the SNPs and their haplotypes with schizophrenia. Therefore, we conclude that GRIK1 does not play a major role in schizophrenia pathogenesis in the Japanese population.
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PMID:Association study of polymorphisms in the GluR5 kainate receptor gene (GRIK1) with schizophrenia. 1170 55

Recent postmortem studies have suggested that changes in the regulation of kainate-sensitive glutamate receptors (kainate receptors) in the hippocampus may play a role in schizophrenia. To explore this possibility further, the distribution of immunoreactivity (IR) for the GluR5,6,7 subunits of the KR was assessed in a cohort consisting of 15 normal controls, 15 schizophrenics, and 9 manic depressives matched for age and postmortem interval (PMI). Cross sections of hippocampus showed abundant GluR5,6,7-IR on apical dendrites of pyramidal neurons in the stratum radiatum and stratum moleculare. In normal controls, both the numerical and length density of IR dendrites were much higher in sector CA2 than in sectors CA3 or CA1. When data for the individual groups were separately examined, the schizophrenics showed a 30-35% reduction in the density of GluR5,6,7-IR dendrites found in both stratum radiatum and stratum moleculare of sectors CA3 and CA2, as well as proximal and middle portions of CA1. In CA2, the magnitude of this decrease in schizophrenia was 2.5 times larger than that seen in any of the other sectors. For the manic depressive group, no significant differences were observed in any sectors or laminae examined. The potential confounding effects of either age, PMI, or neuroleptic exposure do not explain the reduced density of IR dendrites detected in the schizophrenic group. Taken together, the preferential reduction of GluR5,6,7-IR observed on apical dendrites of pyramidal neurons is consistent with a functional downregulation of the kainate receptor in the hippocampus of schizophrenic brain.
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PMID:GluR5,6,7 subunit immunoreactivity on apical pyramidal cell dendrites in hippocampus of schizophrenics and manic depressives. 1173 2

Multiple neurotransmitter systems have been implicated in the pathophysiology of schizophrenia. Dopamine hyperactivity has often been implicated in this illness. More recently, the glutamate hypothesis of schizophrenia suggests that NMDA receptor (NMDAR) hypofunction may also play a role in this illness. This is based primarily on studies showing that phencyclidine, an NMDAR antagonist, can induce a schizophreniform psychosis. While NMDAR dysfunction is most often implicated in schizophrenia, other components of the glutamate system, such as the AMPA and kainate receptors, as well as NMDAR-associated intracellular proteins, may also play a role in regulating NMDA receptor activity and glutamate neurotransmission. There is growing interest in the hypothesis that the pathophysiology of schizophrenia involves alterations in dopamine-glutamate interactions. The glutamate system is anatomically and functionally linked to the dopamine system, and glutamate can modulate dopaminergic activity and release by stimulating various glutamate receptor subtypes expressed by dopaminergic neurons in the substantia nigra/ventral tegmental area. In this study, we investigated dopamine-glutamate interactions by measuring the expression of transcripts encoding the subunits for the ionotropic glutamate receptors (NMDA, AMPA and kainate) and five NMDAR-associated intracellular proteins, PSD-93, PSD-95, SAP102, NF-L and yotiao in the dopaminergic neurons in the substantia nigra pars compacta (SNc) of subjects with schizophrenia and a comparison group. Tyrosine hydroxylase (TH, a marker of dopamine-synthesizing cells), NR1 (an NMDA receptor subunit) and GluR5 (a kainate subunit) transcript levels were significantly increased in the SNc in schizophrenia. These data support the hypothesis that schizophrenia may involve alterations in dopamine-glutamate interactions.
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PMID:Expression of the ionotropic glutamate receptor subunits and NMDA receptor-associated intracellular proteins in the substantia nigra in schizophrenia. 1496 37

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

We utilised postmortem brain tissue to quantify sections of left and right orbitofrontal cortex (area 11) from nine schizophrenic and eight control patients from the Charing Cross Prospective Schizophrenia Study immunostained for the presence of the kainate receptor (GluR5/6/7). The numerical density of neurons immunopositive for kainate receptor was measured. Other sections from the same blocks were stained with cresyl violet to determine the total neuronal numerical density. All measurements were made blind: diagnoses were only revealed by a third party after measurements were completed. There was a significant reduction (21%) in numerical density of kainate receptor-positive neurons in both cortices in the schizophrenic group (488 cells/mm2) compared to that in the control group (618 cells/mm2) (P=0.033). Nissl-stained tissue showed no significant difference in total neuronal numerical density between control and schizophrenic groups. These observations suggest that there are actually fewer kainate receptor-positive neurons in schizophrenic orbitofrontal cortex. There was no correlation of reduced kainate receptor-positive cell number with age at death, postmortem interval, or other possibly confounding neuropathology. Our results support the concept of there being reduced glutamatergic activity in frontal cortex in schizophrenia.
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PMID:Decreased numerical density of kainate receptor-positive neurons in the orbitofrontal cortex of chronic schizophrenics. 1650 99

Pharmacological and anatomical evidence suggests that abnormal glutamate neurotransmission may be associated with the pathophysiology of schizophrenia and mood disorders. Medial temporal lobe structural alterations have been implicated in schizophrenia and to a lesser extent in mood disorders. To comprehensively examine the ionotropic glutamate receptors in these illnesses, we used in situ hybridization to determine transcript expression of N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and kainate receptor subunits in the medial temporal lobe of subjects with schizophrenia, bipolar disorder (BD), or major depression (MDD). We used receptor autoradiography to assess changes in glutamate receptor binding in the same subjects. Our results indicate that there are region- and disorder-specific abnormalities in the expression of ionotropic glutamate receptor subunits in schizophrenia and mood disorders. We did not find any changes in transcript expression in the hippocampus. In the entorhinal cortex, most changes in glutamate receptor expression were associated with BD, with decreased GluR2, GluR3, and GluR6 mRNA expression. In the perirhinal cortex we detected decreased expression of GluR5 in all three diagnoses, of GluR1, GluR3, NR2B in both BD and MDD, and decreased NR1 and NR2A in BD and MDD, respectively. Receptor binding showed NMDA receptor subsites particularly affected in the hippocampus, where MK801 binding was reduced in schizophrenia and BD, and MDL105,519 and CGP39653 binding were increased in BD and MDD, respectively. In the hippocampus AMPA and kainate binding were not changed. We found no changes in the entorhinal and perirhinal cortices. These data suggest that glutamate receptor expression is altered in the medial temporal lobe in schizophrenia and the mood disorders. We propose that disturbances in glutamate-mediated synaptic transmission in the medial temporal lobe are important factors in the pathophysiology of these severe psychiatric illnesses.
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PMID:Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders. 1729 17

The aim of this study was to examine whether glutamatergic inputs onto GABA interneurons via the kainate receptor in the anterior cingulate cortex may be altered in schizophrenia and bipolar disorder. Hence, in a cohort of 60 post-mortem human brains from schizophrenia, bipolar disorder, and normal control subjects, we simultaneously labeled the mRNA for the GluR5 or GluR6 subunit of the kainate receptor with [(35)S] and the mRNA for the 67 kD isoform of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD)(67) with digoxigenin using an immunoperoxidase method. The density of the GAD(67) mRNA-containing neurons that co-expressed GluR5 mRNA was decreased by 43% and 40% in layer 2 of the anterior cingulate cortex in schizophrenia and bipolar disorder, respectively. In contrast, the density of the GAD(67) mRNA-containing cells that expressed GluR6 mRNA was unaltered in either condition. Furthermore, the amount of GluR5 or GluR6 mRNA in the GAD(67) mRNA-expressing cells that contained a detectable level of these transcripts was also unchanged. Finally, the density of cells that did not contain GAD(67) mRNA, which presumably included all pyramidal neurons, but expressed the mRNA for the GluR5 or GluR6 subunit was not altered. Thus, glutamatergic modulation of inhibitory interneurons, but not pyramidal neurons, via kainate receptors containing the GluR5 subunit appears to be selectively altered in the anterior cingulate cortex in schizophrenia and bipolar disorder.
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PMID:Differential alterations of kainate receptor subunits in inhibitory interneurons in the anterior cingulate cortex in schizophrenia and bipolar disorder. 1769 24

Phencyclidine (PCP) induces a form of psychosis that mimics naturally occurring schizophrenia in the most relevant domains of the psychopathology. In this report, we investigated the effect of chronic treatment with PCP on expression and RNA editing of alpha-amino-propionic acid (AMPA) and kainate (KA) glutamate receptor (GluR), in the rat prefrontal cortex and the hippocampus. We found that chronic, but not acute, PCP treatment decreased GluRs expression in the rat prefrontal cortex but not in the hippocampus. In particular, the mRNA coding for GluR2 and GluR3 subunits were reduced by 50%, whereas those coding for KA GluR5 and GluR6 were decreased by 30%. In addition, we observed a decrease of the editing levels of the R/G site in the flop form of both GluR2 and GluR3 and a significant increase in the editing level of GluR6 Q/R site. The variation in the editing level of the R/G sites suggests that chronic PCP treatment induced the formation of glutamate receptor subunits with slower resensitization kinetics and, with respect to kainate receptors, an increase in the Q/R editing level might generate receptor channels with a lower permeability to cations. Combining all the data, it can be inferred that the PCP treatment induced a specific and site-selective reduction of glutamatergic neurotransmission in the prefrontal cortex but not in the hippocampus.
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PMID:Chronic phencyclidine administration reduces the expression and editing of specific glutamate receptors in rat prefrontal cortex. 1770 42


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