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Title page for ETD etd-03122015-212404

Type of Document Dissertation
Author Muller, Christopher Louis
URN etd-03122015-212404
Title Dissecting the Role of the Serotonin Transporter in the Developmental and Neurobehavioral Features of Autism Spectrum Disorder
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Mark Wallace Committee Chair
Alexandre Bonnin Committee Member
Gregg Stanwood Committee Member
Jeremy Veenstra-VanderWeele Committee Member
Randy Blakely Committee Member
  • serotonin transporter
  • autism spectrum disorder
  • mouse model
  • neurodevelopment
Date of Defense 2014-12-01
Availability unrestricted
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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