Date of Award
Spring 4-13-2026
Document Type
Dissertation
Publication Status
Version of Record
Submission Date
April 2026
Department
Biological Sciences
College Granting Degree
Charles E. Schmidt College of Science
Department Granting Degree
Biological Sciences
Degree Name
Doctor of Philosophy (PhD)
Thesis/Dissertation Advisor [Chair]
Randy D. Blakely
Abstract
Autism spectrum disorder (ASD) and major depressive disorder (MDD) are characterized by persistent impairments in social behavior and mood, domains strongly shaped by serotonergic signaling. The serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) is a key determinant of extracellular 5-HT availability, and alterations in SERT function have been strongly implicated in both disorders. Although SERT is viewed primarily as a regulator of 5-HT clearance, how activity dependent regulation shapes serotonergic output during behavior remains unclear. This dissertation examines the functional consequences of phosphorylation-dependent regulation of SERT at Thr276 using the SERT Ala276 mouse model, which selectively disrupts PKG-dependent regulation of the transporter in vivo. Behavioral analyses reveal a sex-specific dissociation in the impact of disrupted Thr276-dependent regulation. Female mice exhibit impairments in sociability, characterized by reduced social preference during repeated social encounters, despite preserved locomotion, affect, and cognitive performance. In contrast, males display altered social dominance without deficits in social preference. These findings indicate that Thr276-dependent SERT regulation supports distinct social behavioral domains across sexes and suggest differential circuit-level reliance on transporter regulation. At the circuit level, in vivo fiber photometry using the genetically encoded 5-HT sensor GRAB5-HT reveals that serotonergic responses to social interaction are disrupted in SERT Ala276 females. While initial 5-HT signaling during social engagement remains intact, serotonergic responses fail to be sustained across subsequent interactions in females. These findings indicate that Thr276-dependent regulation is dispensable for initiating serotonergic signaling but is required to maintain appropriate serotonergic output during repeated social engagement in females. Pharmacological experiments further implicate altered serotonergic feedback as a key mechanism underlying these female-specific phenotypes. Engagement of 5-HT1A autoreceptors with the partial agonist buspirone restores sociability and normalizes serotonergic signaling dynamics, consistent with a model in which impaired transporter regulation enhances autoreceptor-mediated inhibition and constrains serotonergic dynamic range. Finally, nitric oxide signaling emerges as an upstream modulator of PKG-dependent SERT regulation, suggesting that variability in nitrergic tone may influence the engagement of activity-dependent transporter control. Together, this work establishes Thr276-dependent SERT regulation as a state-sensitive mechanism supporting sustained sociability and highlights dynamic transporter modulation as a unifying framework for understanding and ultimately targeting core social dysfunction across neuropsychiatric disorders.
Recommended Citation
Arnold, Carina, "LIMITING SEROTONIN TRANSPORTER PHOSPHORYLATION DISRUPTS cGMP-DEPENDENT SEROTONIN RELEASE AND SOCIAL BEHAVIOR" (2026). Electronic Theses and Dissertations. 244.
https://digitalcommons.fau.edu/etd_general/244