Compromising the phosphodependent regulation of the GABA A R β3 subunit reproduces the core phenotypes of autism spectrum disorders
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 16, 2015
- Source ID
- 10.1073/pnas.1514657112
Entities
People
- Amit Modgil
- Armen M. Abramian
- Jamie Maguire
- Joshua Walker
- Miho Terunuma
- Nicholas J. Brandon
- Paul A. Davies
- Rachel Jurd
- Stephen J. Moss
- Thuy N. Vien
- Uwe Rudolph
Organizations
- AstraZeneca
- Congressionally Directed Medical Research Programs
- Harvard Medical School
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke
- Simons Foundation
- Tufts University
- University College London
- University of Leicester