Compromising the phosphodependent regulation of the GABAAR β3 subunit reproduces the core phenotypes of autism spectrum disorders

Thuy N. Vien, Amit Modgil, Armen M. Abramian, Rachel Jurd, Joshua Walker, Nicholas J. Brandon, Miho Terunuma, Uwe Rudolph, Jamie Maguire, Paul A. Davies, Stephen J. Moss

Research output: Contribution to journalArticlepeer-review

Abstract

Alterations in the efficacy of neuronal inhibition mediated by GABAA receptors (GABAARs) containing β3 subunits are continually implicated in autism spectrum disorders (ASDs). In vitro, the plasma membrane stability of GABAARs 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 GABAARs may directly contribute to the pathophysiology of ASDs.

Original languageEnglish (US)
Pages (from-to)14805-14810
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number48
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

Keywords

  • Autism spectrum disorder
  • GABA receptor
  • Phasic inhibition
  • Phosphorylation
  • Tonic inhibition

ASJC Scopus subject areas

  • General

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