DOI work
Fetched
Post
crossref
Jeremy Veenstra-VanderWeele, Christopher L. Muller, Hideki Iwamoto, Jennifer E. Sauer, W. Anthony Owens, Charisma R. Shah, Jordan Cohen, Padmanabhan Mannangatti, et al.
(2012).
Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior.
Proceedings of the National Academy of Sciences, 109(14), 5469-5474.
National Academy of Sciences.
- Publication date
-
19 Mar 2012
- Identifier
-
10.1073/pnas.1112345109
- Authors
-
Jeremy Veenstra-VanderWeele,
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
- Source
- Proceedings of the National Academy of Sciences
- Details
- 109(14), 5469-5474
- Reference type
- article
- Publisher
- National Academy of Sciences
- Metadata source
- crossref
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.
Study authors in this cited reference