| Summary: | Approximately 25% of individuals with autism spectrum disorder (ASD) possess elevated whole blood serotonin (5-HT) levels, termed hyperserotonemia. However, the connection between this biomarker and the pathophysiology of ASD remains unclear. Several rare, hyperfunctional variants of the serotonin transporter (SERT), a key regulator of 5-HT homeostasis in the periphery and the brain, have been identified in children with ASD. To evaluate the developmental and behavioral consequences of impaired 5-HT signaling, a knock-in mouse model was created that expressed the most frequent of these rare, ASD-associated SERT variants, Gly56Ala. In addition to exhibiting hyperserotonemia and global changes in 5-HT homeostasis in the brain, SERT Ala56 mice display alterations in behavior relevant to the core diagnostic features of ASD. While no changes in the developmental trajectory of the 5-HT system were observed in SERT Ala56 and wildtype littermates, offspring of maternal carriers of the Ala56 variant exhibit a unique pattern of developmental perturbations indicative of impaired placental function. Finally, supporting the original genetic association of the Ala56 variant with sensory aversion, we establish a connection between SERT genetic variation and patterns of sensory behavior in children with ASD. Collectively, these studies provide a foundation for future mechanistic work in the SERT Ala56 mouse model that will elucidate the underlying neurobiological causes of ASD.
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