Modifications in inhibition mediated by gamma-aminobutyric acid type A receptors (GABAAR) are continually implicated in the etiology of autism. GABAAR receptors mediate both phasic (transient) and tonic inhibition (sustained) forms of chloride-ion-mediated neuronal inhibition. Duplications of and mutations within the receptor’s beta-3 subunit are strongly linked to autism. The functional expression of GABAARs is subject to regulation via phosphorylation of serine residues 408 and 409 within the beta-3 subunit, a covalent modification of protein structure that plays a key role in regulating GABAAR activity.
To test the role that altered levels of the beta-3 subunit play in autism, Stephen Moss and his colleagues at Tufts University created mice in which serines 408 and 409 were mutated to alanines (S408/9A). The mice had elevated levels of synaptic phasic inhibition but decreased tonic GABAergic inhibition. The number of dendritic spines, or signal-receiving branches of neurons, was significantly elevated in S408/9A mice, and the researchers observed deficits in social interaction, increased repetitive behavior and enhanced seizure sensitivity.
Moss and his team found that the S408/9A mutation reproduces in mice the core anatomical and behavioral deficits seen in autism. These results suggest that alterations in the activity of beta-3-subunit-containing GABAARs directly contribute to the pathophysiology of autism. The findings also suggest that drugs that act to increase tonic inhibition may be efficacious agents to treat autism.