| Literature DB >> 22431635 |
Jeremy Veenstra-VanderWeele1, Christopher L Muller, Hideki Iwamoto, Jennifer E Sauer, W Anthony Owens, Charisma R Shah, Jordan Cohen, Padmanabhan Mannangatti, Tammy Jessen, Brent J Thompson, Ran Ye, Travis M Kerr, Ana M Carneiro, Jacqueline N Crawley, Elaine Sanders-Bush, Douglas G McMahon, Sammanda Ramamoorthy, Lynette C Daws, James S Sutcliffe, Randy D Blakely.
Abstract
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.Entities:
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Year: 2012 PMID： 22431635 PMCID： PMC3325657 DOI： 10.1073/pnas.1112345109
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205