GABAA Receptor Downregulation in Brains of Subjects with Autism

Abstract

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 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.

Methyl CpG Binding Protein 2 Gene Disruption Augments Tonic Currents of γ-Aminobutyric Acid Receptors in Locus Coeruleus Neurons

“…Both GABA A and GABA B receptormediated postsynaptic inhibition are reduced, and the GABA release from presynaptic terminals is significantly low (10). Consistent with these observations, defects in the GABA A receptor (GABA A R) system are also found in other brain regions (11)(12)(13)(14). Selective deletion of the Mecp2 gene in GABAergic neurons recapitulates most RTT phenotypes in mice (15).…”

“…In postsynaptic cells, there is a marked reduction in GABA A R density in the brain of RTT patients and Mecp2-null mice (34,35). An epigenetic study in a mouse model of RTT indicates that GABA A R ␤3 subunit expression is reduced in the cerebellum, and another molecular study confirmed down-regulation of the ␤3 subunit in the cerebellum (12,36). The ␣1 subunit in the frontal cortex and the ␣2 and ␣4 subunits in the ventrolateral medulla were also reduced in Mecp2-null mice (25).…”

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

“…Additionally, GABAergic dysregulation in the cerebellum has been associated with neuroanatomical abnormalities in the cerebellum. Purkinje cell size and GABAergic protein expression in the cerebellum is reduced in patients with autism (Fatemi et al, 2002;Fatemi et al, 2009 …”

GABA and Glutamate Receptors of the Autistic Brain

“…Posterior studies using different concentrations of [H 3 ]flunitrazepan showed that the decrement of benzodiazepine binding was due to reductions of binding sites with no changes in the binding affinity of the receptors (Guptill et al, 2007). Western blot analyses of four GABA A subunits (1-3 and 3) showed reductions of all subunits in parietal cortex, of 1 in frontal cortex and of 1 and 3 in cerebellum of post-mortem autistic brains (Fatemi et al, 2009). And recent studies showed reductions in the binding sites to muscimol and benzodiazepines in cingulate cortex and fusiform gyrus of autistic brains (Oblak et al, 2009;Oblak et al, 2011).…”