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

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.

Pubmed ID: 22431635


  • 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


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

April 3, 2012

Associated Grants

  • Agency: Autism Speaks, Id: AS2429
  • Agency: NIDA NIH HHS, Id: DA07390
  • Agency: NICHD NIH HHS, Id: HD065278
  • Agency: NICHD NIH HHS, Id: HD15052
  • Agency: NCRR NIH HHS, Id: KL2 RR024977
  • Agency: NIMH NIH HHS, Id: MH078098
  • Agency: NIMH NIH HHS, Id: MH081066
  • Agency: NIMH NIH HHS, Id: MH094604
  • Agency: NIMH NIH HHS, Id: MH62612
  • Agency: NIMH NIH HHS, Id: R01 MH094527
  • Agency: NCRR NIH HHS, Id: RR024975
  • Agency: NCRR NIH HHS, Id: TL1 RR024978
  • Agency: NCRR NIH HHS, Id: UL1 RR024975

Mesh Terms

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