Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior.

Veenstra-VanderWeele J, Muller CL, Iwamoto H, Sauer JE, Owens WA, Shah CR, Cohen J, Mannangatti P, Jessen T, Thompson BJ, Ye R, Kerr TM, Carneiro AM, Crawley JN, Sanders-Bush E, McMahon DG, Ramamoorthy S, Daws LC, Sutcliffe JS, Blakely RD
Proc Natl Acad Sci U S A. 2012 109 (14): 5469-74

PMID: 22431635 · PMCID: PMC3325657 · DOI:10.1073/pnas.1112345109

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.

MeSH Terms (9)

Animals Autistic Disorder Disease Models, Animal Homeostasis Mice Receptors, Serotonin Serotonin Social Behavior Stereotyped Behavior

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