UMLS:C0036341 - FACTA Search

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Single nucleotide polymorphisms in type A gamma-aminobutyric acid (GABA(A)) receptor beta2 subunit gene (GABRB2) were found to be associated with schizophrenia in Chinese, German, Japanese and Portuguese. To explore potential functional consequences of these DNA sequence polymorphisms, this study examined the expression and electrophysiological properties of two alternatively spliced products of GABRB2 along with genotypical disease association analysis. Real-time quantitative polymerase chain reaction, performed with a cohort of 31 schizophrenics and 31 controls of US population, showed 21.7% reduction in the expression of the long isoform beta(2L), 13.4% in the short isoform beta(2S) and 15.8% in the sum of the two isoforms beta(2T) in postmortem schizophrenic brain. Furthermore, two independent mRNA quantitation methods showed that the relative expression of the long over the short isoforms was significantly decreased, suggesting the occurrence of altered splicing, in schizophrenia. In male schizophrenics, the heterozygous genotypes of rs1876071 (T/C) and rs1876072 (A/G) were correlated with reduced expression of beta(2L), beta(2S) and beta(2T), and the heterozygous of rs2546620 (A/G) and homozygous-minor of rs1876071 (C/C) and rs1876072 (G/G) were correlated with reduced expression of beta(2T). Significant correlations of expression levels with different alleles and haplotypes were also indicated by quantitative trait analysis. Recombinant GABA(A) receptors expressed in HEK293 human cells containing beta(2L) underwent a steeper current rundown upon repetitive GABA activation than receptors containing beta(2S). The results thus revealed genotype-dependent expression of the alternatively spliced isoforms of GABA(A) receptor beta2 subunit, giving rise to electrophysiological consequences that could play an important role in the pathogenesis mechanism of schizophrenia.
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PMID:Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: Differential expression and genotypical correlations in schizophrenia. 1698 89

Inhibitory neurotransmission mediated by GABA(A) receptors can be modulated by the endogenous neurosteroids, allopregnanolone and tetrahydro-deoxycorticosterone. Neurosteroids are synthesized de novo in the brain during stress, pregnancyand after ethanol consumption, and disrupted steroid regulation of GABAergic transmission is strongly implicated in several debilitating conditions such as panic disorder, major depression, schizophrenia, alcohol dependence and catamenial epilepsy. Determining how neurosteroids interact with the GABA(A) receptor is a prerequisite for understanding their physiological and pathophysiological roles in the brain. Here we identify two discrete binding sites in the receptor's transmembrane domains that mediate the potentiating and direct activation effects of neurosteroids. They potentiate GABA responses from a cavity formed by the alpha-subunit transmembrane domains, whereas direct receptor activation is initiated by interfacial residues between alpha and beta subunits and is enhanced by steroid binding to the potentiation site. Thus, significant receptor activation by neurosteroids relies on occupancy of both the activation and potentiation sites. These sites are highly conserved throughout the GABA(A )receptor family, and their identification provides a unique opportunity for the development of new therapeutic, neurosteroid-based ligands and transgenic disease models of neurosteroid dysfunction.
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PMID:Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. 1710 70

Changes in GABA(A) receptors are observed in schizophrenia, with benzodiazepine-sensitive GABA(A) receptor subtypes being affected differently to other subtypes. However, long-term antipsychotic drug use in schizophrenia may underlie these changes. To test this, we examined the effects of administering a typical (haloperidol) and an atypical (olanzapine) antipsychotic drug on the GABA(A) receptor agonist (orthosteric) and benzodiazepine (allosteric) binding sites in rat prefrontal cortex. As antipsychotic drugs have delayed maximal therapeutic effects we also examined different drug treatment periods. Male SD rats received a sucrose solution containing either haloperidol (1.5 mg/kg), olanzapine (6.5 mg/kg) or no drug daily for either 7, 14 or 28 days. Sections of rat brain were then labelled with [(3)H]muscimol, which labels the total population of GABA(A) receptors, or the benzodiazepine site ligand [(3)H]flunitrazepam in separate saturation binding experiments using quantitative receptor autoradiography. [(3)H]Muscimol binding was enhanced in the prefrontal cortex after 7 days but no differences were observed after longer periods of drug administration. In contrast there was a delayed increase in density of benzodiazepine-sensitive GABA(A) receptors in the PFC, suggesting that antipsychotic drugs have different effects on different GABA(A) receptor subtypes. These changes in the properties of GABA(A) receptor binding following antipsychotic drug administration are not consistent with those observed in schizophrenia and suggest a 'reshuffling' in GABA(A) receptor subtypes over time.
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PMID:The effects of antipsychotic drugs on GABAA receptor binding depend on period of drug treatment and binding site examined. 1720 12

Rats with neonatal ventral hippocampal lesions (NVHL) have been studied as a neurodevelopmental animal model of schizophrenia. NVHL rats exhibit postpubertal emergence of hyperresponsiveness to stress, suggesting increased mesolimbic dopamine (DA) activity. However, previous studies have not yielded clear evidence of this. Disturbances in the gamma-amino-butyric acid (GABA)-ergic system as well as the dopaminergic system are thought to be present in schizophrenia. To determine whether GABA(A) receptors play a role in the abnormal postpubertal behavior in NVHL rats, we compared changes in expression of mRNA of GABA(A) receptor subunits and in [(35)S] t-butylbicyclophosphorothionate ([(35)S] TBPS) binding in the prepubertal and postpubertal periods. Male pups were lesioned with ibotenic acid at postnatal day 7 (PD 7), and in situ hybridization and quantitative autoradiography were then performed. In NVHL rats, alpha1 subunit mRNA expression in prefrontal cortex was decreased at PD 35 (prepubertal period; by 21.7%), but increased at PD 56 (postpubertal period; by 21.4%) when compared with sham controls. beta2 subunit mRNA expression was increased in PFC in the postpubertal period (by 24.3%). beta3 subunit mRNA expression was increased in the caudate-putamen in the postpubertal period (by 37.2%). [(35)S] TBPS binding was increased in PFC only in the postpubertal period (by 17.7%). These findings suggest that dysfunction of the GABAergic system exists in NVHL rats. Furthermore, developmental and regional changes in GABA(A) receptor expression appear to occur in compensation for the attenuation of GABAergic system activity in NVHL rats.
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PMID:Alterations in GABA(A) receptor expression in neonatal ventral hippocampal lesioned rats: comparison of prepubertal and postpubertal periods. 1737 69

Several studies have suggested the dysfunction of the GABAergic system as a risk factor in the pathogenesis of schizophrenia. In the present study, case-control association analysis was conducted in four GABAergic genes: two glutamic acid decarboxylase genes (GAD1 and GAD2), a GABA(A) receptor subunit beta2 gene (GABRB2) and a GABA(B) receptor 1 gene (GABBR1). Using a universal DNA microarray procedure we genotyped a total of 20 SNPs on the above four genes in a study involving 292 patients and 286 controls of Chinese descent. Statistically significant differences were observed in the allelic frequencies of the rs187269C/T polymorphism in the GABRB2 gene (P=0.0450, chi(2)=12.40, OR=1.65) and the -292A/C polymorphism in the GAD1 gene (P=0.0450, chi(2)=14.64 OR=1.77). In addition, using an electrophoretic mobility shift assay (EMSA), we discovered differences in the U251 nuclear protein binding to oligonucleotides representing the -292 SNP on the GAD1 gene, which suggests that the -292C allele has reduced transcription factor binding efficiency compared with the 292A allele. Using the multifactor-dimensionality reduction method (MDR), we found that the interactions among the rs187269C/T polymorphism in the GABRB2 gene, the -243A/G polymorphism in the GAD2 gene and the 27379C/T and 661C/T polymorphisms in the GAD1 gene revealed a significant association with schizophrenia (P<0.001). These findings suggest that the GABRB2 and GAD1 genes alone and the combined effects of the polymorphisms in the four GABAergic system genes may confer susceptibility to the development of schizophrenia in the Chinese population.
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PMID:Systematic study of association of four GABAergic genes: glutamic acid decarboxylase 1 gene, glutamic acid decarboxylase 2 gene, GABA(B) receptor 1 gene and GABA(A) receptor subunit beta2 gene, with schizophrenia using a universal DNA microarray. 1741 63

In subjects with schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in gamma-aminobutyric acid (GABA)-mediated inhibitory circuitry. To test the hypothesis that altered GABA-mediated circuitry in the DLPFC of subjects with schizophrenia reflects expression changes of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission, we conducted a systematic expression analysis of GABA-related transcripts in the DLPFC of 14 pairs of schizophrenia and age-, sex- and post-mortem interval-matched control subjects using a customized DNA microarray with enhanced sensitivity and specificity. Subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding (1) presynaptic regulators of GABA neurotransmission (67 kDa isoform of glutamic acid decarboxylase (GAD(67)) and GABA transporter 1), (2) neuropeptides (somatostatin (SST), neuropeptide Y (NPY) and cholecystokinin (CCK)) and (3) GABA(A) receptor subunits (alpha1, alpha4, beta3, gamma2 and delta). Real-time qPCR and/or in situ hybridization confirmed the deficits for six representative transcripts tested in the same pairs and in an extended cohort, respectively. In contrast, GAD(67), SST and alpha1 subunit mRNA levels, as assessed by in situ hybridization, were not altered in the DLPFC of monkeys chronically exposed to antipsychotic medications. These findings suggest that schizophrenia is associated with alterations in inhibitory inputs from SST/NPY-containing and CCK-containing subpopulations of GABA neurons and in the signaling via certain GABA(A) receptors that mediate synaptic (phasic) or extrasynaptic (tonic) inhibition. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia is mediated by altered GABA neurotransmission in certain DLPFC microcircuits.
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PMID:Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. 1747 Dec 87

The gamma-aminobutyric acid type-A (GABA(A)) receptor plays a major role in inhibitory neurotransmissions. Intronic SNPs and haplotypes in GABRB2, the gene for GABA(A) receptor beta(2) subunit, are associated with schizophrenia and correlated with the expression of two alternatively spliced beta(2) isoforms. In the present study, using chimpanzee as an ancestral reference, high frequencies were observed for the derived (D) alleles of the four SNPs rs6556547, rs187269, rs1816071 and rs1816072 in GABRB2, suggesting the occurrence of positive selection for these derived alleles. Coalescence-based simulation showed that the population frequency spectra and the frequencies of H56, the haplotype having all four D alleles, significantly deviated from neutral-evolution expectation in various demographic models. Haplotypes containing the derived allele of rs1816072 displayed significantly less diversity compared to haplotypes containing its ancestral allele, further supporting positive selection. The variations in DD-genotype frequencies in five human populations provided a snapshot of the evolutionary history, which suggested that the positive selections of the D alleles are recent and likely ongoing. The divergence between the DD-genotype profiles of schizophrenic and control samples pointed to the schizophrenia-relevance of positive selections, with the schizophrenic samples showing weakened selections compared to the controls. These DD-genotypes were previously found to increase the expression of beta(2), especially its long isoform. Electrophysiological analysis showed that this long beta(2) isoform favored by the positive selections is more sensitive than the short isoform to the inhibition of GABA(A) receptor function by energy depletion. These findings represent the first demonstration of positive selection in a schizophrenia-associated gene.
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PMID:Positive selection within the Schizophrenia-associated GABA(A) receptor beta(2) gene. 1752 21

Post-mortem studies of the human brain indicate that certain GABA(A) receptor subtypes may be differentially altered in schizophrenia. Increased binding to the total population of GABA(A) receptors using [3H]muscimol is observed in the post-mortem schizophrenic brain, yet a proportion of these receptors which bind benzodiazepines and are labelled with [3H]flunitrazepam, show decreased or unaltered expression. Data from animal studies suggest that antipsychotic drugs alter GABA(A) receptor expression in a subtype selective manner, but in the opposite direction to that observed in schizophrenia. To broaden our understanding of the effects of antipsychotic drugs on GABA(A) receptors, we examined the saturation binding maximum (B(max)) and binding affinity (K(D)) of [3H]muscimol and [3H]flunitrazepam in the prefrontal cortex (PFC), hippocampus and thalamus of male SD rats that received a sucrose solution containing either haloperidol (1.5 mg/kg), olanzapine (6.5 mg/kg) or no drug daily for up to 28 days using quantitative receptor autoradiography. [3H]Muscimol binding density was increased most prominently in the PFC after 7 days, with larger and more prolonged effects being induced by the atypical antipsychotic drug olanzapine in subcortical regions. While no changes were observed in [3H]muscimol binding in any region after 28 days of drug administration, [3H]flunitrazepam binding density (B(max)) was increased for both antipsychotic treatments in the PFC only. These findings confirm that the subset of GABA(A) receptors sensitive to benzodiazepines are regulated differently from other GABA(A) receptor subtypes following antipsychotic drug administration, in a time- and region-dependent manner.
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PMID:Antipsychotic drug administration differentially affects [3H]muscimol and [3H]flunitrazepam GABA(A) receptor binding sites. 1797 80

A significant body of data suggests that GABA(A) receptors are altered in the CNS of subjects with schizophrenia. However, subjects with schizophrenia are treated with antipsychotic drugs and, in some cases, antipsychotic drugs and benzodiazepines. It has therefore been suggested that the changes in GABA(A) receptors in the CNS of subjects with schizophrenia are due to such drug treatments. Surprisingly, there appear to be no studies to determine the effect of a combined antipsychotic-benzodiazepine treatment on GABA(A) receptors. We therefore measured both the GABA binding site ([3H]muscimol) and the benzodiazepine binding site ([3H]flumazenil) in the CNS of rats treated with either haloperidol, diazepam or a combination of the two drugs. The main findings of our study are that treatment with diazepam or the combination of diazepam and haloperidol results in regionally selective increases GABA binding sites but treatment with haloperidol alone decreases the GABA binding site in the thalamus but increases these sites in the hypothalamus. By contrast, treatment with diazepam, haloperidol and a combination of the two drugs resulted in widespread decreases in the number of benzodiazepine binding sites in the rat CNS. The notable exception to this outcome was increased numbers of benzodiazepine binding sites in the frontal cortex of rats that had received diazepam. Our data suggests that there are complex changes in the GABA(A) receptor following treatment with haloperidol, diazepam or a combination of these drugs. This outcome may be relevant to the therapeutic benefits of using both drugs in conjunction early in the treatment of a psychotic episode.
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PMID:Treatment with haloperidol and diazepam alters GABA(A) receptor density in the rat brain. 1804 61

The role of postsynaptic nicotinic receptors for acetylcholine (nAChRs) in mediating fast neurotransmission processes in the CNS is controversial. Here we have studied the modulation of synaptic transmission by an agonist (choline) and an allosteric modulator (5-OH-indole) of alpha7 nAChRs in rat hippocampal neuronal cultures. Choline evoked a fast inactivating inward current, causing neuron depolarization and action potential discharge, thereby enhancing the spontaneous postsynaptic current activity (sPSCs). This effect was markedly enhanced when both choline and 5-OH-indole were applied together and was blocked by the selective alpha7 nAChR antagonist methyllycaconitine. This choline action was suppressed by the GABA(A) receptor antagonist bicuculline, while the glutamatergic receptor antagonist kynurenic acid had no effect. Frequency, but not amplitude or area, of both excitatory and inhibitory miniature postsynaptic currents (mEPSCs and mIPSCs) were drastically reduced when Ca(2+) influx was blocked by Cd(2+). Additionally, nAChR activation did not modify the mIPSCs. These data suggest that Ca(2+) influx through the highly Ca(2+)-permeablealpha7 nAChRs was insufficient to directly activate neurotransmitter release, suggesting that a tight colocalization of this receptor with secretory hot spots is unlikely. In a few cases, the activation of alpha7 AChRs led to a suppression of spontaneous synaptic transmission. This effect may be related to the potentiation of GABAergic interneurons that inhibit the spontaneous activity of neurons making synapses with the cell under study. We suggest that GABA release is modulated by alpha7 nAChRs. Thus, selective allosteric modulators of alpha7 nAChRs could have potential therapeutic applications in brain disorders such as epilepsy and schizophrenia and in alterations of cognition and sensory processing.
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PMID:Allosteric modulation of alpha 7 nicotinic receptors selectively depolarizes hippocampal interneurons, enhancing spontaneous GABAergic transmission. 1831 91

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