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

J Veenstra-VanderWeele, CL Muller… - Proceedings of the …, 2012 - National Acad Sciences
J Veenstra-VanderWeele, CL Muller, H Iwamoto, JE Sauer, WA Owens, CR Shah, J Cohen…
Proceedings of the National Academy of Sciences, 2012National Acad Sciences
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 …
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 5HT1A and 5HT2A 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.
National Acad Sciences