GABA and Schizophrenia: A Review of Basic Science and Clinical Studies

Wassef, Adel; Baker, J. D.; Kochan, Lisa D.

doi:10.1097/01.jcp.0000095349.32154.a5

Cited by 223 publications

(158 citation statements)

References 212 publications

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“…[47][48][49] The current study has presented several lines of evidence for the specific involvement of GABA A receptor subunit genes located in the 5q schizophrenia risk locus. We detected association between schizophrenia and both GABRA1 and GABRP in a patient sample of Portuguese descent.…”

Section: Discussionmentioning

confidence: 72%

“…42 The 5q GABA genes are plausible candidates for the schizophrenia risk gene in the 5q locus based on a converging body of literature implicating GABA system dysfunction in schizophrenia pathophysiology. [43][44][45][46][47][48][49] In schizophrenia patient brain samples, markers of GABAergic neurons are reduced in expression and postsynaptic receptor complexes are increased in number. 47,50,51 Furthermore, there is evidence that neuregulin 1 (NRG1) and dysbindin (DTNBP1), two schizophrenia candidate risk genes, 33,[52][53][54][55][56][57][58][59][60][61][62][63][64][65] interact with the GABA A receptor.…”

Section: Introductionmentioning

confidence: 99%

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Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia

et al. 2005

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We previously performed a genome-wide linkage scan in Portuguese schizophrenia families that identified a risk locus on chromosome 5q31-q35. This finding was supported by metaanalysis of 20 other schizophrenia genome-wide scans that identified 5q23.2-q34 as the second most compelling susceptibility locus in the genome. In the present report, we took a two-stage candidate gene association approach to investigate a group of gamma-aminobutyric acid (GABA) A receptor subunit genes (GABRA1, GABRA6, GABRB2, GABRG2, and GABRP) within our linkage peak. These genes are plausible candidates based on prior evidence for GABA system involvement in schizophrenia. In the first stage, associations were detected in a Portuguese patient sample with single nucleotide polymorphisms (SNPs) and haplotypes in GABRA1 (P ¼ 0.00062-0.048), GABRP (P ¼ 0.0024-0.042), and GABRA6 (P ¼ 0.0065-0.0088). The GABRA1 and GABRP findings were replicated in the second stage in an independent German family-based sample (P ¼ 0.0015-0.043). Supportive evidence for association was also obtained for a previously reported GABRB2 risk haplotype. Exploratory analyses of the effects of associated GABRA1 haplotypes on transcript levels found altered expression of GABRA6 and coexpressed genes of GABRA1 and GABRB2. Comparison of transcript levels in schizophrenia patients and unaffected siblings found lower patient expression of GABRA6 and coexpressed genes of GABRA1. Interestingly, the GABRA1 coexpressed genes include synaptic and vesicle-associated genes previously found altered in schizophrenia prefrontal cortex. Taken together, these results support the involvement of the chromosome 5q GABA A receptor gene cluster in schizophrenia, and suggest that schizophrenia-associated haplotypes may alter expression of GABA-related genes.

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Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia

et al. 2005

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“…Despite substantive evidence of impaired GABA neurotransmission in SCZ (Wassef et al, 2003), no previous study has directly associated GABGR3 to the disorder.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide investigation of schizophrenia associated plasma Ndel1 enzyme activity

Gadelha

Coleman

Breen

et al. 2016

Schizophrenia Research

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“…Abnormal glutamatergic signaling has been a prominent 'hypothesis' about the pathophysiology of schizophrenia, 29,30 and it has been suggested that a number of the genes currently implicated in schizophrenia are related to NMDA (N-methyl-D-aspartate) signaling in the brain. [31][32][33] An equally prominent hypothesis involves gamma-aminobutyric acid (GABA) neuronal function, [34][35][36][37] but this avenue has been relatively unexplored from a genetic perspective. The recent demonstration that loss of NRG1/ERBB4 signaling alters the tangential migration of cortical interneurons and reduces the number of GABAergic interneurons in post-natal cortex 38 is potentially a quite important mechanistic lead, since statistical evidence suggests that these two genes may synergistically increase the risk for schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression

et al. 2007

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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 0 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 0 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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GABA and Schizophrenia: A Review of Basic Science and Clinical Studies

Cited by 223 publications

References 212 publications

Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia

Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia

Genome-wide investigation of schizophrenia associated plasma Ndel1 enzyme activity

Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression

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