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

TLDR

Increased whole‑blood serotonin and SERT gene variants have long been linked to autism spectrum disorders, suggesting disrupted serotonin homeostasis may contribute to ASD risk. Transgenic mice carrying the SERT Ala56 gain‑of‑function variant exhibit p38 MAPK‑dependent hyperphosphorylation of the transporter, accelerated serotonin clearance, and hyperserotonemia, along with altered raphe neuron firing and heightened 5‑HT1A/5‑HT2A receptor sensitivity. These mice display deficits in social interaction, communication, and increased repetitive behaviors, supporting the role of serotonin dysregulation in ASD traits and offering a valid model for further mechanistic and therapeutic studies.

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.