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

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

Research output: Contribution to journalArticle

188 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5469-5474
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number14
DOIs
StatePublished - Apr 3 2012

Keywords

  • Development
  • Monoamine
  • Neurotransmitter

ASJC Scopus subject areas

  • General

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    Veenstra-VanderWeele, J., Muller, C. L., Iwamoto, H., Sauer, J. E., Owens, W. A., Shah, C. R., Cohen, J., Mannangatti, P., Jessen, T., Thompson, B. J., Ye, R., Kerr, T. M., Carneiro, A. M., Crawley, J. N., Sanders-Bush, E., McMahon, D. G., Ramamoorthy, S., Daws, L. C., Sutcliffe, J. S., & Blakely, R. D. (2012). Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior. Proceedings of the National Academy of Sciences of the United States of America, 109(14), 5469-5474. https://doi.org/10.1073/pnas.1112345109