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Compromising the phosphodependent regulation of the GABA A R β3 subunit reproduces the core phenotypes of autism spectrum disorders
- Source :
- Proceedings of the National Academy of Sciences. 112:14805-14810
- Publication Year :
- 2015
- Publisher :
- Proceedings of the National Academy of Sciences, 2015.
-
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.
- Subjects :
- Male
Kainic acid
medicine.medical_specialty
Dendritic spine
Autism Spectrum Disorder
Dendritic Spines
Biology
Hippocampus
Mice
chemistry.chemical_compound
GABA receptor
Internal medicine
mental disorders
Serine
medicine
Animals
Biotinylation
Gene Knock-In Techniques
Phosphorylation
Social Behavior
Receptor
gamma-Aminobutyric Acid
Alanine
Epilepsy
Multidisciplinary
Behavior, Animal
GABAA receptor
Cell Membrane
Electroencephalography
Fear
Biological Sciences
Receptors, GABA-A
FMR1
Molecular biology
Electrophysiological Phenomena
Mice, Inbred C57BL
Disease Models, Animal
Phenotype
Endocrinology
Gene Expression Regulation
chemistry
Mutation
Synapses
Convulsant
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 112
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....0b47e0dc6db85d338f0840e57f7a1dce