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)

Among the most consistent results of studies of post-mortem brain tissue from schizophrenia patients (SZP) is the finding that in this disease, several genes expressed by GABAergic neurons are downregulated. This downregulation may be caused by hypermethylation of the relevant promoters in affected neurons. Indeed, increased numbers of GABAergic interneurons expressing DNA methyltransferase 1 (DNMT1) mRNA have been demonstrated in the prefrontal cortex (PFC) of SZP using in situ hybridization. The present study expands upon these findings using nested competitive reverse transcription-polymerase chain reaction combined with laser-assisted microdissection to quantitate the extent of DNMT1 mRNA overexpression in distinct populations of GABAergic neurons obtained from either layer I or layer V of the PFC of SZP. In a cohort of eight SZP and eight non-psychiatric subject (NPS) post-mortem BA9 tissue samples, DNMT1 mRNA was found to be selectively expressed in GABAergic interneurons and virtually absent in pyramidal neurons. DNMT1 mRNA expression was approximately threefold higher in GABAergic interneurons microdissected from layer I of SZP relative to the same neurons microdissected from NPS. GABAergic interneurons obtained from layer V of the same samples displayed no difference in DNMT1 mRNA expression between groups. In the same samples, the GABAergic neuron-specific glutamic acid-decarboxylase(67) (GAD(67)) and reelin mRNAs were underexpressed twofold in GABAergic interneurons isolated from layer I of SZP relative to GABAergic interneurons microdissected from layer I of NPS, and unaltered in GABAergic interneurons of layer V. These findings implicate an epigenetically mediated layer I GABAergic dysfunction in the pathogenesis of schizophrenia, and suggest novel strategies for treatment of the disease.
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PMID:Selective epigenetic alteration of layer I GABAergic neurons isolated from prefrontal cortex of schizophrenia patients using laser-assisted microdissection. 1726 40

Postmortem studies regarding schizophrenia revealed altered expression of genes related to gamma-amino butyric acid neurotransmission system. One of the most consistent findings is the reduced level of 67 kDa glutamic acid decarboxylase isoform (GAD(67)). Moreover, several studies reported positive associations between the GAD(67) gene (GAD1) and schizophrenia. These reasons, motivated us to carry out replication study regarding association between GAD1 (fourteen tagging SNPs) and schizophrenia in Japanese population (562 schizophrenic patients and 470 controls). However we couldn't confirm significant association that had been previously reported. Considering size of our sample and strategy that corresponds well with the approaches used in gene-based association analysis, our conclusion is that GAD1 does not play a major role in schizophrenia in Japanese population.
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PMID:No association between the glutamate decarboxylase 67 gene (GAD1) and schizophrenia in the Japanese population. 1730 89

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

GABAergic dysfunction is present in the hippocampus in schizophrenia (SZ) and bipolar disorder (BD). The trisynaptic pathway was "deconstructed" into various layers of sectors CA3/2 and CA1 and gene expression profiling performed. Network association analysis was used to uncover genes that may be related to regulation of glutamate decarboxylase 67 (GAD(67)), a marker for this system that has been found by many studies to show decreased expression in SZs and BDs. The most striking change was a down-regulation of GAD(67) in the stratum oriens (SO) of CA2/3 in both groups; CA1 only showed changes in the SO of schizophrenics. The network generated for GAD(67) contained 25 genes involved in the regulation of kainate receptors, TGF-beta and Wnt signaling, as well as transcription factors involved in cell growth and differentiation. In SZs, IL-1beta, (GRIK2/3), TGF-beta2, TGF-betaR1, histone deacetylase 1 (HDAC1), death associated protein (DAXX), and cyclin D2 (CCND2) were all significantly up-regulated, whereas in BDs, PAX5, Runx2, LEF1, TLE1, and CCND2 were significantly down-regulated. In the SO of CA1 of BDs, where GAD67 showed no expression change, TGF-beta and Wnt signaling genes were all up-regulated, but other transcription factors showed no change in expression. In other layers/sectors, BDs showed no expression changes in these GAD(67) network genes. Overall, these results are consistent with the hypothesis that decreased expression of GAD(67) may be associated with an epigenetic mechanism in SZ. In BD, however, a suppression of transcription factors involved in cell differentiation may contribute to GABA dysfunction.
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PMID:Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars. 1755 60

Cortical GABAergic dysfunction has been implicated as a key component of the pathophysiology of schizophrenia and decreased expression of the gamma-aminobutyric acid (GABA) synthetic enzyme glutamic acid decarboxylase 67 (GAD(67)), encoded by GAD1, is found in schizophrenic post-mortem brain. We report evidence of distorted transmission of single-nucleotide polymorphism (SNP) alleles in two independent schizophrenia family-based samples. In both samples, allelic association was dependent on the gender of the affected offspring, and in the Clinical Brain Disorders Branch/National Institute of Mental Health (CBDB/NIMH) sample it was also dependent on catechol-O-methyltransferase (COMT) Val158Met genotype. Quantitative transmission disequilibrium test analyses revealed that variation in GAD1 influenced multiple domains of cognition, including declarative memory, attention and working memory. A 5' flanking SNP affecting cognition in the families was also associated in unrelated healthy individuals with inefficient BOLD functional magnetic resonance imaging activation of dorsal prefrontal cortex (PFC) during a working memory task, a physiologic phenotype associated with schizophrenia and altered cortical inhibition. In addition, a SNP in the 5' untranslated (and predicted promoter) region that also influenced cognition was associated with decreased expression of GAD1 mRNA in the PFC of schizophrenic brain. Finally, we observed evidence of statistical epistasis between two SNPs in COMT and SNPs in GAD1, suggesting a potential biological synergism leading to increased risk. These coincident results implicate GAD1 in the etiology of schizophrenia and suggest that the mechanism involves altered cortical GABA inhibitory activity, perhaps modulated by dopaminergic function.
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PMID:Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression. 1776 49

The disorganized symptoms of schizophrenia, including severely disordered thought patterns, may be indicative of a problem with the construction and maintenance of cell assemblies during sensory processing and attention. The gamma and beta frequency bands (15-70 Hz) are believed relevant to such processing. This paper addresses the results of an experimental examination of the cortical response of 12 schizophrenia patients and 12 control subjects when presented with auditory click-train stimuli in the gamma/beta frequency band during measurement using magnetoencephalography (MEG), as well as earlier work by Kwon et al. These data indicate that control subjects show an increased 40-Hz response to both 20- and 40-Hz stimulation as compared with patients, whereas schizophrenic subjects show a preference for 20-Hz response to the same driving frequencies. In this work, two computational models of the auditory cortex are constructed based on postmortem studies that indicate cortical interneurons in schizophrenic subjects have decreased GAT-1 (a GABA transporter) and GAD(67) (1 of 2 enzymes responsible for GABA synthesis). The models transition from control to schizophrenic frequency response when an extended inhibitory decay time is introduced; this change captures a possible effect of these GABA alterations. Modeling gamma/beta range auditory entrainment in schizophrenia provides insight into how biophysical mechanisms can impact cognitive function. In addition, the study of dynamics that underlie auditory entrainment in schizophrenia may contribute to the understanding of how gamma and beta rhythms impact cognition in general.
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PMID:Modeling GABA alterations in schizophrenia: a link between impaired inhibition and altered gamma and beta range auditory entrainment. 1828 55

Knowledge concerning the classification of mental disorders progressed substantially with the use of DSM III-IV and IDCD 10 because it was based on observed data, with precise definitions. These classifications a priori avoided to generate definitions related to etiology or treatment response. They are based on a categorical approach where diagnostic entities share common phenomenological features. Modifications proposed or discussed are related to the weak validity of the classification strategy described above. (a) Disorders are supposed to be independent but the current coexistence of two or more disorders is the rule; (b) They also are supposed to have stability, however anxiety disorders most of the time precede major depression. For GAD age at onset, family history, biology and symptomatology are close to those of depression. As a consequence broader entities such as depression-GAD spectrum, panic-phobias spectrum and OCD spectrum including eating disorders and pathological gambling are taken into consideration; (c) Diagnostic categories use thresholds to delimitate a border with normals. This creates "subthreshold" conditions. The relevance of such conditions is well documented. Measuring the presence and severity of different dimensions, independent from a threshold, will improve the relevance of the description of patients pathology. In addition, this dimensional approach will improve the problems posed by the mutually exclusive diagnoses (depression and GAD, schizophrenia and depression); (d) Some disorders are based on the coexistence of different dimensions. Patients may present only one set of symptoms and have different characteristics, evolution and response to treatment. An example would be negative symptoms in Schizophrenia; (e) Because no etiological model is available and most measures are subjective, objective measures (cognitive, biological) and genetics progresses created important hopes. None of these measures is pathognomonic and most appear to be related to risk factors especially at certain periods when associated with environmental events. One of the major aims for a classification of patients is to identify groups to whom a best possible therapeutic strategy can be proposed. Drugs may improve fear extinction while the genetic and/or acquired avoidance may be called phobia. The basic mechanism and or the corresponding phenotype should appear in the classification. Progresses in early identification of disturbances by taking into account all the information available (prodromal symptoms, cognitive, biological, imaging, genetic, family information) are crucial for the future therapeutic strategy: prevention.
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PMID:Refinement of diagnosis and disease classification in psychiatry. 1834 44

Postmortem studies have shown that schizophrenia produces a reduction in the 67-kilodalton isoform of glutamic acid decarboxylase (GAD67), a key enzyme for gamma-aminobutyric acid (GABA) synthesis. N-methyl-d-aspartate receptor (NMDAR) antagonists have been extensively used to study schizophrenia because they can induce many aspects of the disease, including the decrease in GAD67. It is generally thought that this reduction in GAD implies a reduction in functional inhibition, but direct evidence had been lacking. We have therefore performed physiological studies in slices of prefrontal cortex taken from rats treated with the NMDAR antagonist ketamine. Both frequency and amplitude of miniature inhibitory postsynaptic currents were reduced. Consistent with a reduction of inhibition, we observed an increase in postsynaptic excitability. The increased excitability is likely to result from disinhibition because miniature excitatory postsynaptic current properties and intrinsic excitability were not changed. Ketamine did not affect inhibition or GAD levels in young rats, indicating a developmental regulation that may be related to the developmental increase in ketamine sensitivity that occurs in humans. Our results show that NMDAR antagonist produces biochemical changes in the GABA system that lead to a functional disinhibition. Such disinhibition would be expected to decrease gamma oscillations, which are reduced in schizophrenia.
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PMID:Prolonged exposure to NMDAR antagonist suppresses inhibitory synaptic transmission in prefrontal cortex. 1852 22

Tobacco smoking is frequently abused by schizophrenia patients (SZP). The major synaptically active component inhaled from cigarettes is nicotine, hence the smoking habit of SZP may represent an attempt to use nicotine self-medication to correct (i) a central nervous system nicotinic acetylcholine receptor (nAChR) dysfunction, (ii) DNA-methyltransferase 1 (DMT1) overexpression in GABAergic neurons, and (iii) the down-regulation of reelin and GAD(67) expression caused by the increase of DNMT1-mediated hypermethylation of promoters in GABAergic interneurons of the telencephalon. Nicotine (4.5-22 micromol/kg s.c., 4 injections during the 12-h light cycle for 4 days) decreases DNMT1 mRNA and protein and increases GAD(67) expression in the mouse frontal cortex (FC). This nicotine-induced decrease of DNMT1 mRNA expression is greater (80%) in laser microdissected FC layer I GABAergic neurons than in the whole FC (40%), suggesting selectivity differences for the specific nicotinic receptor populations expressed in GABAergic neurons of different cortical layers. The down-regulation of DNMT1 expression induced by nicotine in the FC is also observed in the hippocampus but not in striatal GABAergic neurons. Furthermore, these data show that in the FC, the same doses of nicotine that decrease DNMT1 expression also (i) diminished the level of cytosine-5-methylation in the GAD(67) promoter and (ii) prevented the methionine-induced hypermethylation of the same promoter. Pretreatment with mecamylamine (6 micromol/kg s.c.), an nAChR blocker that penetrates the blood-brain barrier, prevents the nicotine-induced decrease of FC DNMT1 expression. Taken together, these results suggest that nicotine, by activating nAChRs located on cortical or hippocampal GABAergic interneurons, can up-regulate GAD(67) expression via an epigenetic mechanism. Nicotine is not effective in striatal medium spiny GABAergic neurons that primarily express muscarinic receptors.
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PMID:Nicotine decreases DNA methyltransferase 1 expression and glutamic acid decarboxylase 67 promoter methylation in GABAergic interneurons. 1885 56

Animals with a neonatal ventral hippocampal lesion (NVHL) develop abnormal behaviors during or after adolescence, suggesting that early insults can have delayed consequences. Many of these behaviors depend on the prefrontal cortex (PFC), and we have reported that PFC pyramidal neurons of adult rats with an NVHL respond to stimulation of the ventral tegmental area with an increase in firing instead of the characteristic decrease. As the dopamine modulation of cortical interneurons matures during adolescence, these findings raise the possibility that maturation of local inhibitory circuits within the PFC may have been altered in NVHL rats. Here, we assessed the state of PFC interneurons in NVHL rats with in situ hybridization measures of the mRNAs for the calcium binding protein parvalbumin (PV) and the GABA synthesizing enzyme GAD(67), as well as with electrophysiological measures of interneuron function. Although no differences were observed with PV or GAD(67), whole-cell recordings in slices revealed abnormal responses to the D(2) agonist quinpirole in interneurons from NVHL rats. The loss of D(2) modulation of local inhibition in slices from NVHL rats was also evident in the absence of a lasting component in the D(2) attenuation of excitatory synaptic responses in pyramidal neurons, which in sham treated rats was picrotoxin sensitive. The results suggest that the neonatal lesion causes improper maturation, but not loss, of PFC interneurons during adolescence, a finding consistent with current interpretations of imaging data in schizophrenia that suggest a hyperactive, "noisy" cortex underlying dysfunction in the PFC and other cortical areas.
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PMID:A neonatal ventral hippocampal lesion causes functional deficits in adult prefrontal cortical interneurons. 1903 62

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