Compromising the phosphodependent regulation of the GABA A R β3 subunit reproduces the core phenotypes of autism spectrum disorders

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-12, Vol.112 (48), p.14805-14810
• Main Authors: Vien, Thuy N., Modgil, Amit, Abramian, Armen M., Jurd, Rachel, Walker, Joshua, Brandon, Nicholas J., Terunuma, Miho, Rudolph, Uwe, Maguire, Jamie, Davies, Paul A., Moss, Stephen J.
• Format: Article
• Language: English
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1514657112

Alterations in the efficacy of neuronal inhibition mediated by GABA A receptors (GABA A Rs) containing β3 subunits are continually implicated in autism spectrum disorders (ASDs). In vitro, the plasma membrane stability of GABA A Rs is potentiated via phosphorylation of serine residues 408 and 409 (S408/9) in the β3 subunit, an effect that is mimicked by their mutation to alanines. Here, we created a mouse in which S408/9 have been mutated to alanines (S408/9A). S408/9A mice exhibited altered dendritic spine structure, increased repetitive behavior, decreased social interaction, and an epileptic phenotype. Thus, mutation of S408/9 reproduces the core deficits seen in humans with ASDs. Collectively, our results suggest that alterations in phosphorylation and/or activity of β3-containing GABA A Rs may directly contribute to the pathophysiology of ASDs. Alterations in the efficacy of neuronal inhibition mediated by GABA A receptors (GABA A Rs) containing β3 subunits are continually implicated in autism spectrum disorders (ASDs). In vitro, the plasma membrane stability of GABA A Rs is potentiated via phosphorylation of serine residues 408 and 409 (S408/9) in the β3 subunit, an effect that is mimicked by their mutation to alanines. To assess if modifications in β3 subunit expression contribute to ASDs, we have created a mouse in which S408/9 have been mutated to alanines (S408/9A). S408/9A homozygotes exhibited increased phasic, but decreased tonic, inhibition, events that correlated with alterations in the membrane stability and synaptic accumulation of the receptor subtypes that mediate these distinct forms of inhibition. S408/9A mice exhibited alterations in dendritic spine structure, increased repetitive behavior, and decreased social interaction, hallmarks of ASDs. ASDs are frequently comorbid with epilepsy, and consistent with this comorbidity, S408/9A mice exhibited a marked increase in sensitivity to seizures induced by the convulsant kainic acid. To assess the relevance of our studies using S408/9A mice for the pathophysiology of ASDs, we measured S408/9 phosphorylation in Fmr1 KO mice, a model of fragile X syndrome, the most common monogenetic cause of ASDs. Phosphorylation of S408/9 was selectively and significantly enhanced in Fmr1 KO mice. Collectively, our results suggest that alterations in phosphorylation and/or activity of β3-containing GABA A Rs may directly contribute to the pathophysiology of ASDs.