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)

A recent postmortem study has reported that there is a widespread upregulation of GABA(A) receptor binding activity throughout most subregions of the hippocampal formation of schizophrenic brain. The current study has been undertaken to determine whether the benzodiazepine (BZ) receptor, which is a component of the GABA(A) receptor complex, may also be upregulated in schizophrenics. Using a low-resolution film autoradiographic technique to localize [3H]flunitrazepam binding, the subregional and laminar distribution of specific BZ receptor binding was found to parallel that of the GABA(A) site, except in the area dentata where BZ binding was approximately 73% higher in the outer molecular layer. When BZ receptor binding was compared in the same normal control (n = 15) and schizophrenic (n = 8) cases in which the GABA(A) receptor was analyzed, there were very few differences noted between the two groups, except for small, though significant, increases in the stratum oriens of CA3 (30%), the subiculum (20-30%) and the presubiculum (15-20%) of the patient group. These latter increases overlapped with the subregions and laminae in schizophrenics showing the most marked increases of GABA(A) receptor binding. Using a high-resolution technique to evaluate specific BZ receptor binding on different neuronal subtypes, no difference was observed on either pyramidal or nonpyramidal neurons of sector CA3 where GABA(A) receptor activity had been found to be significantly increased on the latter neuronal subtype. The potential confounding effects of age, postmortem interval and exposure to either benzodiazepine or neuroleptic drugs do not account for the lack of marked differences in BZ receptor binding in the schizophrenic group. Taken together, the results of this study are consistent with the possibility that defective GABAergic integration in schizophrenia may be associated with an uncoupling in the regulation of the GABA(A) and BZ receptors.
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PMID:Uncoupling of GABA(A) and benzodiazepine receptor binding activity in the hippocampal formation of schizophrenic brain. 916 47

The proteins expressed by a genome have been termed the proteome. Comparative proteome analysis of brain tissue offers a novel means to identify biologically significant gene products that underlie psychopathology. In this study we collected post mortem hippocampal tissue from the brains of seven schizophrenic, seven Alzheimer's disease (AD) and seven control individuals. Hippocampal proteomes were visualised by two-dimensional gel electrophoresis of homogenised tissue. A mean of 549 (s.d. 35) proteins were successfully matched between each disease group and the control group. In comparison with the control hippocampal proteome, eight proteins in the schizophrenic hippocampal proteome were found to be decreased and eight increased in concentration, whereas, in the AD hippocampal proteome, 35 proteins were decreased and 73 were increased in concentration (P<0.05). One protein, which was decreased in concentration in both diseases, was characterised as diazepam binding inhibitor (DBI) by N-terminal sequence analysis. DBI can regulate the action of the GABA(A) receptor. Protein changes involved 6% of the assessed AD hippocampal proteome, whereas, in schizophrenia protein changes involved less than 1% of the assessed hippocampal proteome. We conclude that schizophrenia has a subtle neuropathological presentation and comparative proteome analysis is a viable means by which to investigate diseases of the brain at the molecular level.
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PMID:A comparative proteome analysis of hippocampal tissue from schizophrenic and Alzheimer's disease individuals. 1020 49

The hypothesis that the pathophysiology of schizophrenia may be associated with a dysfunction in GABA transmission in the human prefrontal cortex was investigated. Human post mortem brain tissue from 10 control cases and six cases of schizophrenia were processed for amino acid analysis and for radioactive in situ hybridization. Laminae III and V of three prefrontal cortical areas were examined in detail, namely Brodmann areas 9, 10 and 11. Of these three areas significant changes in GABAergic markers were found only in areas 9 and 10. Of note, a significant decrease in the tissue content of GABA was observed and this was accompanied by a marked increase in the cellular expression of the GABA(A) receptor alpha-1 subunit messenger RNA and a marked decrease in the expression of human GABA transporter-1, the messenger RNA encoding the neuronal GABA transporter protein. The amino acid analysis data provided in this study coupled with the detailed cellular study of several GABAergic markers in the human prefrontal cortex provide direct evidence in support of a disturbance in GABA transmission in the prefrontal cortex, which may be loosely termed "hypofrontality".
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PMID:Measurement of GABAergic parameters in the prefrontal cortex in schizophrenia: focus on GABA content, GABA(A) receptor alpha-1 subunit messenger RNA and human GABA transporter-1 (HGAT-1) messenger RNA expression. 1046 26

Recent biochemical observations have suggested the abnormalities in the gamma-amino-butyric acid (GABA)ergic system in schizophrenic brains. In the present study, we investigated the subunits gene expressions and ligand binding of the GABA(A) receptor following acute and chronic administration of phencyclidine (PCP), which induces schizophrenia-like symptoms, in rats using in situ hybridization and in vitro quantitative autoradiography. PCP i.p. administration at a daily dose of 7.5 mg/kg resulted in a significant decrease in expression of alpha 1 subunit mRNA in cerebral cortices (cingulate (-13%) and temporal cortex (-6%)) and hippocampal formation (CA1 (-11%), CA2 (-10%), CA3 (-11%) and dentate gyrus (-12%)) 1 h after a single treatment. In the repeated PCP administrations for 14 days, the expression of beta 2 mRNA in the cerebellum (-10%) and of beta 3 mRNA in the cerebral cortices (cingulate (-12%), parietal (-16%) and temporal cortex (-16%), caudate putamen (-18%), inferior colliculus (-18%), and cerebellum (-15%) were significantly decreased. In addition, [(35)S]t-butylbicyclophosphorothionate (TBPS) binding was also reduced in layer IV of the frontoparietal cortex (-14%), inferior colliculus (-17%), and cerebellum (-12%) following chronic PCP treatment, while no changes were observed following acute PCP treatment. These results indicate that single and repeated administrations of PCP independently regulate the expression of GABA(A)/benzodiazepine (BZD) receptor subunits mRNA and its receptor binding in the brain.
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PMID:Differential expression of GABA(A) receptor subunit mRNAs and ligand binding sites in rat brain following phencyclidine administration. 1094 Nov 40

Abnormalities in amygdala and hippocampus have been shown to coexist in schizophrenia (SZ). In the hippocampus, compelling evidence suggests that a disruption of GABA neurotransmission is present mainly in sectors CA4, CA3, and CA2. The amygdala sends important inputs to the hippocampus and is also believed to have a defective GABA system in schizophrenia. To explore the possibility that changes in the hippocampal GABAergic system could be related to an increased inflow of activity originating in the amygdala, a "partial" animal model has been developed. In awake, freely moving, rats a GABA(A) receptor antagonist was infused locally into the basolateral nuclear complex of the amygdala (BLn). Within 2 hours, a decreased density of both the 65- and 67-kDa isoforms of glutamate decarboxylase (GAD(65) and GAD(67)) -immunoreactive (IR) terminals was detected on neuron somata in sectors CA3 and CA2, but not in CA1, CA3, or dentate gyrus. An increase of GAD(67)-IR somata was also found in the dentate gyrus and CA4. In anterograde tracer studies, amygdalo-hippocampal projection fibers were exclusively found in CA3 and CA2, but not CA1. Taken together, these results indicate that activation of amygdalo-hippocampal afferents is associated with the induction of significant changes in the GABA system of the hippocampus, with a subregional distribution that is remarkably similar to that found in SZ. Under pathologic conditions, an excessive discharge of excitatory activity emanating from the amygdala could be capable of altering inhibitory modulation along the trisynaptic pathway. This mechanism may potentially contribute to disturbances of GABAergic function in the major psychoses. Such "partial" rodent modelling provides an important strategy for deciphering the effect of altered cortico-limbic circuits in SZ.
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PMID:Amygdalar activation alters the hippocampal GABA system: "partial" modelling for postmortem changes in schizophrenia. 1116 95

Several lines of evidence have implicated prenatal stress and the hippocampal GABA system in the pathophysiology of schizophrenia, and prenatal stress is believed to increase the risk for schizophrenia through alterations of this neurotransmitter. To explore this hypothesis, we treated male rats pre- and/or postnatally (P48 and P60) with either corticosterone (CORT) or vehicle to establish three study groups: VVV, receiving vehicle at all three time points; VCC, receiving vehicle prenatally and CORT at both postnatal timepoints; and CCC, receiving CORT at all three timepoints. Animals were sacrificed at either 24 h or 5 days after final injection and examined for mRNA levels of GAD65, GAD67, and the GABA(A) receptor subunits alpha2 and gamma2. At 24 h, GAD65 mRNA was decreased in CA1, CA2, CA4, and dentate gyrus (DG) of VCC rats; this effect was either decreased or reversed in CCC-treated animals. No effect was detected in GAD67 mRNA at 24 h. At 5 days, CORT treatment increased GAD67 mRNA levels in CA1, CA3, and DG. Prenatal treatment with CORT was associated with increased responsiveness only in CA3 and DG. For the GABAA receptor, alpha2 subunit mRNA did not show any change in response to CORT treatment, while that for the gamma2 subunit was decreased in CA2 of both VCC- and CCC-treated animals. Consistent with gamma2 subunit mRNA decreases, benzodiazepine (BZ) receptor binding activity was decreased in CA2 with CORT treatment. Prenatal CORT exposure neither increased nor decreased this effect. These results demonstrate that CORT administration is associated with a complex regulation of mRNA expression for pre- and postnatal aspects of the hippocampal GABA system. Under these conditions, prenatal exposure to CORT may sensitize some of these effects, but does not fundamentally alter the nature of this response.
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PMID:Effects of pre- and postnatal corticosterone exposure on the rat hippocampal GABA system. 1173 3

Schizophrenia is currently thought to be associated with a hypoglutamatergic state that is mimicked by acute phencyclidine (PCP), an antagonist of the N-methyl-D-aspartate (NMDA) receptor subtype. In this study we tested the hypothesis that chronic treatment of rats with this antagonist may be a more appropriate animal model than acute exposure since it could result in adaptive synaptic responses that would model certain aspects of the schizophrenic state in humans. In vitro intracellular electrophysiological recordings employing brain slices from rats treated chronically in vivo with PCP demonstrated that chronic PCP caused a substantial increase in synaptic responses mediated by NMDA receptors without any significant changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-mediated synaptic responses. At the same time, GABA(A) receptor-mediated inhibitory responses were depressed significantly. Pharmacological and paired-pulse facilitation experiments demonstrated that these adaptive responses following chronic PCP administration were not the result of altered glutamate or GABA release. Immunoblot analyses suggest that the hyperfunctional NMDA response is at least partially mediated by an increased synthesis of NR1 and NR2A subunits as well as a change in the subunit stoichiometry of the NMDA receptor. This change in receptor composition was also supported by pharmacological experiments with a subunit selective NMDA antagonist. Our data support a reconsideration of NMDA and GABA(A) receptor responsiveness following a chronic, not acute, exposure to PCP and the adaptations that persist after such a regimen.
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PMID:Adaptation to chronic PCP results in hyperfunctional NMDA and hypofunctional GABA(A) synaptic receptors. 1212 79

In the prefrontal cortex of subjects with schizophrenia, markers of the synthesis and re-uptake of GABA appear to be selectively altered in a subset of interneurons that includes chandelier cells. Determining the effect of these disturbances in presynaptic GABA markers on inhibitory signaling requires knowledge of the status of GABA(A) receptors at the postsynaptic targets of chandelier cells, the axon initial segments (AIS) of pyramidal neurons. Because the alpha(2) subunit of the GABA(A) receptor is preferentially localized at pyramidal neuron AIS, we quantified alpha(2) subunit immunoreactive AIS in tissue sections containing prefrontal cortex area 46 from 14 matched triads of subjects with schizophrenia, subjects with major depression and control subjects. Systematic, random sampling revealed that the mean number of alpha(2)-labeled AIS per mm(2) in subjects with schizophrenia was significantly (P = 0.007) increased by 113% compared to control subjects and non-significantly increased compared to subjects with major depression. Furthermore, within subjects with schizophrenia, the density of alpha(2)-labeled AIS was negatively correlated (r = -0.49, P = 0.038) with the density of chandelier axon terminals immunoreactive for the GABA membrane transporter. These data suggest that GABA(A) receptors are up-regulated at pyramidal neuron AIS in response to deficient GABA neuro-transmission at chandelier axon terminals in schizophrenia. Thus, disturbances in inhibition at the chandelier neuron-pyramidal neuron synapse may be a critical component of prefrontal cortical dysfunction in schizophrenia.
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PMID:Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. 1221 70

The dorsal (DRN) and median raphe nuclei (MRN) are two major sources of serotonergic projections to forebrain that are involved in regulation of behavioral state and motor activity, and implicated in affective disorders such as depression and schizophrenia. To investigate afferent influences on serotonergic neurons, this study compared the role of endogenous GABA and glutamate in the DRN and MRN using microdialysis and measurement of locomotor activity in freely behaving rats. Local infusion of the GABA(A) receptor antagonist bicuculline increased serotonin (5-HT) efflux in the DRN but not the MRN. In contrast, infusion of glutamate receptor antagonists produced larger decreases in 5-HT efflux in the MRN compared with the DRN. Moreover, glutamate receptor antagonists attenuated the increase in 5-HT efflux produced by GABA receptor blockade in the DRN. Thus, the disinhibitory effect of GABA blockers could be ascribed in part to an enhanced influence of glutamate. Measurements of locomotor activity indicate that changes in 5-HT were not simply correlated with behavioral activity induced by drug infusion. In summary, the role of inhibitory and excitatory afferents was strikingly different in the DRN and MRN. GABA afferents were the predominant tonic influence on serotonergic neurons in the DRN. In contrast, glutamatergic but not GABAergic afferents had a strong tonic influence on serotonergic neurons in the MRN.
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PMID:Influence of inhibitory and excitatory inputs on serotonin efflux differs in the dorsal and median raphe nuclei. 1253 83

Disturbances in GABAergic system have been observed in schizophrenics. In the present study, population association analysis was performed on 19 SNPs in the alpha(1), beta(2), gamma(2), epsilon and pi subunit genes of GABA(A) receptor. Five SNPs in GABRB2, namely B2I7G1584T, rs1816071, rs194072, rs252944 and rs187269, were found to be significantly associated, and their haplotypes in linkage disequilibrium, with schizophrenia. This represents the first report on any disease association of SNPs in the human GABA(A) receptor genes, and focuses attention on the GABAergic hypothesis of schizophrenia etiology.
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PMID:Association of SNPs and haplotypes in GABAA receptor beta2 gene with schizophrenia. 1469 26


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