dc.creator | Muller, Christopher Louis | |
dc.date.accessioned | 2020-08-21T21:08:29Z | |
dc.date.available | 2017-03-25 | |
dc.date.issued | 2015-03-25 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-03122015-212404 | |
dc.identifier.uri | http://hdl.handle.net/1803/10744 | |
dc.description.abstract | 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. | |
dc.format.mimetype | application/pdf | |
dc.subject | serotonin transporter | |
dc.subject | autism spectrum disorder | |
dc.subject | mouse model | |
dc.subject | neurodevelopment | |
dc.title | Dissecting the Role of the Serotonin Transporter in the Developmental and Neurobehavioral Features of Autism Spectrum Disorder | |
dc.type | dissertation | |
dc.contributor.committeeMember | Randy Blakely | |
dc.contributor.committeeMember | Gregg Stanwood | |
dc.contributor.committeeMember | Alexandre Bonnin | |
dc.contributor.committeeMember | Jeremy Veenstra-VanderWeele | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Neuroscience | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2017-03-25 | |
local.embargo.lift | 2017-03-25 | |
dc.contributor.committeeChair | Mark Wallace | |