The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Schahram Akbarian - One of the best experts on this subject based on the ideXlab platform.
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transcriptional regulation of GAD1 gaba synthesis gene in the prefrontal cortex of subjects with schizophrenia
Schizophrenia Research, 2015Co-Authors: Amanda Mitchell, Yan Jiang, Cyril J Peter, Schahram AkbarianAbstract:Expression of GAD1 GABA synthesis enzyme is highly regulated by neuronal activity and reaches mature levels in the prefrontal cortex not before adolescence. A significant portion of cases diagnosed with schizophrenia show deficits in GAD1 RNA and protein levels in multiple areas of adult cerebral cortex, possibly reflecting molecular or cellular defects in subtypes of GABAergic interneurons essential for network synchronization and cognition. Here, we review 20years of progress towards a better understanding of disease-related regulation of GAD1 gene expression. For example, deficits in cortical GAD1 RNA in some cases of schizophrenia are associated with changes in the epigenetic architecture of the promoter, affecting DNA methylation patterns and nucleosomal histone modifications. These localized chromatin defects at the 5' end of GAD1 are superimposed by disordered locus-specific chromosomal conformations, including weakening of long-range promoter-enhancer loopings and physical disconnection of GAD1 core promoter sequences from cis-regulatory elements positioned 50 kilobases further upstream. Studies on the 3-dimensional architecture of the GAD1 locus in neurons, including developmentally regulated higher order chromatin compromised by the disease process, together with exploration of locus-specific epigenetic interventions in animal models, could pave the way for future treatments of psychosis and schizophrenia.
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prefrontal dysfunction in schizophrenia involves mixed lineage leukemia 1 regulated histone methylation at gabaergic gene promoters
The Journal of Neuroscience, 2007Co-Authors: Hsiensung Huang, Anouch Matevossian, Catheryne Whittle, Se Young Kim, Armin Schumacher, Stephen P Baker, Schahram AkbarianAbstract:Alterations in GABAergic mRNA expression play a key role for prefrontal dysfunction in schizophrenia and other neurodevelopmental disease. Here, we show that histone H3-lysine 4 methylation, a chromatin mark associated with the transcriptional process, progressively increased at GAD1 and other GABAergic gene promoters (GAD2, NPY, SST) in human prefrontal cortex (PFC) from prenatal to peripubertal ages and throughout adulthood. Alterations in schizophrenia included decreased GAD1 expression and H3K4-trimethylation, predominantly in females and in conjunction with a risk haplotype at the 5′ end of GAD1. Heterozygosity for a truncated, lacZ knock-in allele of mixed-lineage leukemia 1 (Mll1), a histone methyltransferase expressed in GABAergic and other cortical neurons, resulted in decreased H3K4 methylation at GABAergic gene promoters. In contrast, GAD1 H3K4 (tri)methylation and Mll1 occupancy was increased in cerebral cortex of mice after treatment with the atypical antipsychotic, clozapine. These effects were not mimicked by haloperidol or genetic ablation of dopamine D2 and D3 receptors, suggesting that blockade of D2-like signaling is not sufficient for clozapine-induced histone methylation. Therefore, chromatin remodeling mechanisms at GABAergic gene promoters, including MLL1-mediated histone methylation, operate throughout an extended period of normal human PFC development and play a role in the neurobiology of schizophrenia.
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GAD1 mrna expression and dna methylation in prefrontal cortex of subjects with schizophrenia
PLOS ONE, 2007Co-Authors: Hsiensung Huang, Schahram AkbarianAbstract:Dysfunction of prefrontal cortex in schizophrenia includes changes in GABAergic mRNAs, including decreased expression of GAD1, encoding the 67 kDa glutamate decarboxylase (GAD67) GABA synthesis enzyme. The underlying molecular mechanisms remain unclear. Alterations in DNA methylation as an epigenetic regulator of gene expression are thought to play a role but this hypothesis is difficult to test because no techniques are available to extract DNA from GAD1 expressing neurons efficiently from human postmortem brain. Here, we present an alternative approach that is based on immunoprecipitation of mononucleosomes with anti-methyl-histone antibodies differentiating between sites of potential gene expression as opposed to repressive or silenced chromatin. Methylation patterns of CpG dinucleotides at the GAD1 proximal promoter and intron 2 were determined for each of the two chromatin fractions separately, using a case-control design for 14 schizophrenia subjects affected by a decrease in prefrontal GAD1 mRNA levels. In controls, the methylation frequencies at CpG dinucleotides, while overall higher in repressive as compared to open chromatin, did not exceed 5% at the proximal GAD1 promoter and 30% within intron 2. Subjects with schizophrenia showed a significant, on average 8-fold deficit in repressive chromatin-associated DNA methylation at the promoter. These results suggest that chromatin remodeling mechanisms are involved in dysregulated GABAergic gene expression in schizophrenia.
A F Markham - One of the best experts on this subject based on the ideXlab platform.
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homozygosity for a missense mutation in the 67 kda isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy parallels with stiff person syndrome and other movement disorders
BMC Neurology, 2004Co-Authors: Clare N Lynex, Ian M Carr, J P Leek, Rajgopal Achuthan, Simon Mitchell, Eamonn R Maher, Geoffrey C Woods, David T Bonthon, A F MarkhamAbstract:Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts.
Katharina Domschke - One of the best experts on this subject based on the ideXlab platform.
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epigenetic signature of panic disorder a role of glutamate decarboxylase 1 GAD1 dna hypomethylation
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2013Co-Authors: Katharina Domschke, Nicola Tidow, Marie Schrempf, Kathrin Schwarte, Benedikt Klauke, Andreas Reif, Anette Kersting, Volker AroltAbstract:Glutamate decarboxylases (GAD67/65; GAD1/GAD2) are crucially involved in gamma-aminobutyric acid (GABA) synthesis and thus were repeatedly suggested to play an important role in the pathogenesis of anxiety disorders. In the present study, DNA methylation patterns in the GAD1 and GAD2 promoter and GAD1 intron 2 regions were investigated for association with panic disorder, with particular attention to possible effects of environmental factors. Sixty-five patients with panic disorder (f=44, m=21) and 65 matched healthy controls were analyzed for DNA methylation status at 38 GAD1 promoter/intron2 and 10 GAD2 promoter CpG sites via direct sequencing of sodium bisulfate treated DNA extracted from blood cells. Recent positive and negative life events were ascertained. Patients and controls were genotyped for GAD1 rs3762556, rs3791878 and rs3762555, all of which are located in the analyzed promoter region. Patients with panic disorder exhibited significantly lower average GAD1 methylation than healthy controls (p<0.001), particularly at three CpG sites in the promoter as well as in intron 2. The occurrence of negative life events was correlated with relatively decreased average methylation mainly in the female subsample (p=0.01). GAD1 SNP rs3762555 conferred a significantly lower methylation at three GAD1 intron 2 CpG sites (p<0.001). No differential methylation was observed in the GAD2 gene. The present pilot data suggest a potentially compensatory role of GAD1 gene hypomethylation in panic disorder possibly mediating the influence of negative life events and depending on genetic variation. Future studies are warranted to replicate the present finding in independent samples, preferably in a longitudinal design.
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gender differences in associations of glutamate decarboxylase 1 gene GAD1 variants with panic disorder
PLOS ONE, 2012Co-Authors: Heike Weber, Katharina Domschke, Benedikt Klauke, Claus Jurgen Scholz, Christian Baumann, Christian Jacob, Wolfgang Maier, Jurgen Fritze, Borwin BandelowAbstract:Background: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females. Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n=478; replication sample n=584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype6gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype6gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score. Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder.
Clare N Lynex - One of the best experts on this subject based on the ideXlab platform.
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homozygosity for a missense mutation in the 67 kda isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy parallels with stiff person syndrome and other movement disorders
BMC Neurology, 2004Co-Authors: Clare N Lynex, Ian M Carr, J P Leek, Rajgopal Achuthan, Simon Mitchell, Eamonn R Maher, Geoffrey C Woods, David T Bonthon, A F MarkhamAbstract:Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts.
Po-hsiu Kuo - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the interaction between genetic variants of GAD1 and mirna in bipolar disorders
Journal of Affective Disorders, 2017Co-Authors: Yu Chu Ella Chung, Shao Chien Chen, Li Chung Chuang, Weiliang Shih, Yi Hang Chiu, Hsichung Chen, Po-hsiu KuoAbstract:Abstract Background Glutamic acid dehydrogenase 1 (GAD1) serves as the rate-limiting enzyme for synthesizing GABA, and is reported to be associated with several psychiatric disorders. The present study examined the effects of GAD1 genetic variants on bipolar disorder (BD) and its subtypes. Moreover, we investigated functional interactions between genetic variants and miRNAs via algorithm prediction and experimental validation. Methods A case-control study was conducted with 280 BD patients and 200 healthy controls. Eight tag SNPs in GAD1 were genotyped. For associated markers, we performed in silico prediction for their potential functions through SNP-miRNA interactions by establishing a scoring system to combine information from several miRNA predictive algorithms. We then tested allelic expression differences using Dual-Glo luciferase reporter assays for the selected SNP-miRNA pair. Lastly, we examined the associations of the GAD1 gene and BD in two additional independent datasets with a few thousand samples for replication. Results Marker rs3749034 was associated with BD, in particular the BD-II subtype. According to our scoring system, several candidate miRNAs were predicted to interact with rs3749034, and hsa-miR-504 had the highest score. Findings from an in vitro experiment revealed a non-statistically significant trend for lower gene expression level with the A allele of rs3749034 compared with the G allele. The association between rs3749034 and BD was not replicated in either of the independent datasets. Instead, other rarer genetic variants in GAD1 showed suggestive signals (e.g. rs575441409, p-value = 3.8*10 −4 , D′ = 1 with rs3749034) with BD in the Taiwanese dataset. Limitations The present study considered common genetic variants only. In addition, we only used a 293 T cell-line in conducting luciferase reporter assays, as no primary cell-lines from patient samples were available to differentiate the effects between BD subtypes. Conclusions Our results demonstrate a weak effect of the GAD1 gene on the risk of bipolar illness, and the associated marker might represent a proxy for real signals of rare variants.
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Associations of glutamate decarboxylase genes with initial sensitivity and age-at-onset of alcohol dependence in the Irish Affected Sib Pair Study of Alcohol Dependence.
Drug and Alcohol Dependence, 2008Co-Authors: Po-hsiu Kuo, Gursharan Kalsi, Carol A. Prescott, Colin A. Hodgkinson, David Goldman, Jeffry Alexander, Edwin J. C. G. Van Den Oord, Xiangning Chen, Patrick F. Sullivan, Diana G. PattersonAbstract:Background The relation of γ-aminobutyric acid (GABA) to alcohol dependence (AD) has been widely studied. Several previous studies suggest that GABA may be involved in alcohol withdrawal, tolerance, and the symptoms that form an AD diagnosis. The genes coding for glutamate decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis, are of potential interest for their association to ethanol consumption and AD. There are two isoforms of GAD, GAD1 and GAD2, which were reported to be associated with AD in males of Han Taiwanese (GAD1) and Russian (GAD2) ancestry. The present study examined the association of the two GAD isoforms with AD and relevant alcohol-related traits in the Irish Affected Sib Pair Study of Alcohol Dependence [Prescott, C.A., Sullivan, P.F., Myers, J.M., Patterson, D.G., Devitt, M., Halberstadt, L.J., Walsh, D., Kendler, K.S., 2005. The Irish Affected Sib Pair Study of Alcohol Dependence: study methodology and validation of diagnosis by interview and family history. Alcohol.-Clin. Exp. Res. 29 (3) 417–429].