title: Compromising the phosphodependent regulation of the GABAAR β3 subunit reproduces the core phenotypes of autism spectrum disorders.
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.
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111;
authors.forename: Thuy N
authors.initials: TN
authors.lastname: Vien
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111;
authors.forename: Amit
authors.initials: A
authors.lastname: Modgil
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111;
authors.forename: Armen M
authors.initials: AM
authors.lastname: Abramian
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111;
authors.forename: Rachel
authors.initials: R
authors.lastname: Jurd
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111;
authors.forename: Joshua
authors.initials: J
authors.lastname: Walker
authors.affiliation: AstraZeneca Neuroscience iMed, Cambridge, MA 02139;
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
authors.affiliation: Department of Cell Physiology and Pharmacology, University of Leicester, Leicester LE1 9HN, United Kingdom;
authors.forename: Miho
authors.initials: M
authors.lastname: Terunuma
authors.affiliation: Laboratory of Genetic Neuropharmacology, McLean Hospital, and Department of Psychiatry, Harvard Medical School, Belmont, MA 02478;
authors.forename: Uwe
authors.initials: U
authors.lastname: Rudolph
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111;
authors.forename: Jamie
authors.initials: J
authors.lastname: Maguire
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111;
authors.forename: Paul A
authors.initials: PA
authors.lastname: Davies
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111; Department of Neuroscience, Physiology, and Pharmacology, University College, London WC1E 6BT, United Kingdom stephen.moss@tufts.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
mesh_terms: D000409:Alanine / Q000235:genetics; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000378:metabolism*; D001522:Behavior, Animal; D019921:Biotinylation; D002462:Cell Membrane / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism; D004195:Disease Models, Animal; D004569:Electroencephalography; D055724:Electrophysiological Phenomena; D004827:Epilepsy / Q000150:complications; D005239:Fear; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D011963:Receptors, GABA-A / Q000235:genetics*; D012694:Serine / Q000235:genetics; D012919:Social Behavior; D013569:Synapses / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C546270:Gabrb3 protein, mouse; D011963:Receptors, GABA-A; D012694:Serine; D005680:gamma-Aminobutyric Acid; D000409:Alanine
keywords: GABA receptor; autism spectrum disorder; phasic inhibition; phosphorylation; tonic inhibition