Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 14, Pages 5469-5474Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1112345109
Keywords
development; monoamine; neurotransmitter
Categories
Funding
- National Institutes of Health (NIH) [MH081066, MH094604, DA07390, MH078098, HD065278, MH62612, HD15052, RR024975]
- Autism Speaks Pilot Award
- American Academy of Child and Adolescent Psychiatry
- Seaside Therapeutics
- Roche Pharmaceuticals
- Novartis
- Forest Pharmaceuticals
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Fifty years ago, increased whole-blood serotonin levels, or hyperserotonemia, first linked disrupted 5-HT homeostasis to Autism Spectrum Disorders (ASDs). The 5-HT transporter (SERT) gene (SLC6A4) has been associated with whole blood 5-HT levels and ASD susceptibility. Previously, we identified multiple gain-of-function SERT coding variants in children with ASD. Here we establish that transgenic mice expressing the most common of these variants, SERT Ala56, exhibit elevated, p38 MAPK-dependent transporter phosphorylation, enhanced 5-HT clearance rates and hyperserotonemia. These effects are accompanied by altered basal firing of raphe 5-HT neurons, as well as 5HT(1A) and 5HT(2A) receptor hypersensitivity. Strikingly, SERT Ala56 mice display alterations in social function, communication, and repetitive behavior. Our efforts provide strong support for the hypothesis that altered 5-HT homeostasis can impact risk for ASD traits and provide a model with construct and face validity that can support further analysis of ASD mechanisms and potentially novel treatments.
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