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.
Proceedings of the National Academy of Sciences of the United States of America
April 3, 2012
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
Disease Models, Animal
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