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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Acknowledgments Human tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders; the Harvard Brain Tissue Resource Center, which is supported in part by PHS grant number R24 MH068855; the Brain Endowment Bank, which is funded in part by the National Parkinson Foundation, Inc., Miami, Florida; and the Autism Tissue Program and is gratefully acknowledged. Grant support by Eunice Kennedy Shriver National Institute of Child Health and Human Development (#5R01HD052074-01A2) to SHF is gratefully acknowledged.
All experimental procedures were approved by the Institutional Review Board of the University of Minnesota School of Medicine. Postmortem blocks of parietal cortex (BA40), superior frontal cortex (BA9), and cerebellum (lobar origin unknown) were obtained from the Autism Research Foundation and various brain banks (NICHD Brain and Tissue Bank for Developmental Disorders; TARF; the Harvard Brain Tissue Resource Center, which is supported in part by PHS grant number R24 MH068855; the Brain Endowment Bank, which is funded in part by the National Parkinson Foundation, Inc., Miami, Florida; and the Autism Tissue Program). These samples, which have been used by our laboratory previously, are some of the most well-characterized and most-studied brain collections used by multiple groups (for review, see Palmen et al. 2004). Before being frozen, donated brains were sectioned in half, dissected by anatomists and placed in labeled bags. All samples were stored at -80°C until use. Samples were derived from three groups of subjects (cerebellum: N = 5–6 from subjects with autism, N = 7–9 from control subjects; BA9: N = 4–6 from subjects with autism, N = 3 from control subjects; BA40: N = 6–8 from subjects with autism, N = 5–6 from control subjects). Consent from next of kin was given to the respective institutions. DSM-IV diagnoses were established prior to death by neurologists and psychiatrists using information from all available medical records and from family interviews. Details regarding the subject selection, diagnostic process, and tissue processing were collected by the Autism Research Foundation. Samples were matched for age, gender, and postmortem interval (PMI). All demographic information is listed in Table 1. Seven out of nine subjects with autism had seizure disorder, and all subjects with autism displayed varying degrees of mental retardation (personal communication from Dr. Margaret Bauman). None of the controls had any known history of neuropsychiatric disorders, seizure disorder, or mental retardation.