GABAA Receptor Downregulation in Brains of Subjects with Autism

School of Medicine, University of Minnesota Department of Neuroscience Minneapolis MN USA
Journal of Autism and Developmental Disorders (Impact Factor: 3.34). 02/2008; 39(2):223-230. DOI: 10.1007/s10803-008-0646-7


Gamma-aminobutyric acid A (GABAA) receptors are ligand-gated ion channels responsible for mediation of fast inhibitory action of GABA in the brain. Preliminary
reports have demonstrated altered expression of GABA receptors in the brains of subjects with autism suggesting GABA/glutamate
system dysregulation. We investigated the expression of four GABAA receptor subunits and observed significant reductions in GABRA1, GABRA2, GABRA3, and GABRB3 in parietal cortex (Brodmann’s
Area 40 (BA40)), while GABRA1 and GABRB3 were significantly altered in cerebellum, and GABRA1 was significantly altered in
superior frontal cortex (BA9). The presence of seizure disorder did not have a significant impact on GABAA receptor subunit expression in the three brain areas. Our results demonstrate that GABAA receptors are reduced in three brain regions that have previously been implicated in the pathogenesis of autism, suggesting
widespread GABAergic dysfunction in the brains of subjects with autism.

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    • "Because these disorders are only diagnosable in patients, the human brain becomes by necessity the primary object of investigation. A clear example of the success of this strategy is the involvement of GABAergic interneurons in the pathophysiology of disorders such as schizophrenia, bipolar disorder and autism (Benes et al., 1992; Akbarian et al., 1995; Woo et al., 1998; Lewis et al., 1999; Benes, 2000; Volk et al., 2000; Benes and Berretta, 2001; Cotter et al., 2002; Heckers et al., 2002; Costa et al., 2004; Guidotti et al., 2005; Lewis et al., 2005; Torrey et al., 2005; Akbarian and Huang, 2006; Fatemi et al., 2009; Lawrence et al., 2010; Blatt and Fatemi, 2011; Fatemi et al., 2011; Guidotti et al., 2011) (see also articles included in this Special Issue). The postulated role of the GABA system in schizophrenia, the main focus of this Special Issue, has originated from a variety of technological approaches to the study of the human brain that include both in vivo brain imaging and postmortem investigations of the human brain. "
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    • "Changes in GABA neurotransmission by KGD might explain the decrease in seizure frequencies and improved behavior observed in Rett syndrome (106). Studies in patients with ASD strongly suggest a dysfunction in the GABAergic system (107–109). However, changes in other components (including Gly, taurine, and GABA) cannot be excluded (34). "
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    • "A recent study reported significantly increased variance of GABRB3 expression in the brain of patients with 15q11-13 duplication compared to control subjects and patients with autism [15]. Nevertheless, our findings are different from several postmortem studies that showed reduced GABRB3 expression in the brains of patients with autism [14-16,60]. Hence, the clinical relevance of our findings in this study remains to be clarified. "
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    ABSTRACT: BackgroundGABRB3 is a position candidate gene at chromosome 15q12 that has been implicated in the neurobiology of autism spectrum disorders (ASD). The aim of this study was to examine the genetic association of GABRB3 with ASD.MethodsThe sample consisted of 356 patients with clinical diagnosis of ASD according to the DSM-IV diagnostic criteria and confirmed by the Autism Diagnostic Interview-Revised and 386 unrelated controls. We searched for mutations at all the exonic regions and 1.6 Kb of the 5′ region of GABRB3 in the genomic DNA of all the participants using the Sanger sequencing. We implemented a case-control association analysis of variants detected in this sample, and conducted a reporter gene assay to assess the functional impact of variants at the 5′ regulatory region.ResultsWe detected six known common SNPs; however, they were not associated with ASD. Besides, a total of 22 rare variants (12 at 5′ regulatory, 4 at intronic, and 6 at exonic regions) were detected in 18 patients and 6 controls. The frequency of rare variants was significantly higher in the patient group than in the control group (18/356 versus 6/386, odds ratio = 3.37, P = 0.007). All the 12 rare variants at the 5′ regulatory region were only detected in 7 patients, but not in any of the controls (7/356 versus 0/386, Fisher’s exact test, P = 0.006). Two patients carried multiple rare variants. Family studies showed that most of these rare variants were transmitted from their parents. Reporter gene assays revealed that four rare variants at the 5′ regulatory region and 1 at exon 1a untranslated region had elevated reporter gene activities compared to two wild type alleles.ConclusionsOur data suggest rare variants of GABRB3 might be associated with ASD, and increased GABRB3 expression may contribute to the pathogenesis of ASD in some patients.Trial registrationClinical trial registration Identifier: NCT00494754
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