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Title page for ETD etd-05232017-122303


Type of Document Dissertation
Author Zike, Isaac Daniel
Author's Email Address isaac.d.zike@vanderbilt.edu
URN etd-05232017-122303
Title Investigating the Role of Obsessive-Compulsive Disorder Candidate Gene SLC1A1 in Basal Ganglia and Repetitive Behavior
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Ariel Deutch Committee Chair
Carrie Jones Committee Member
Gregg Stanwood Committee Member
James Bodfish Committee Member
Jeremy Veenstra-VanderWeele Committee Member
Keywords
  • obsessive
  • compulsive
  • glutamate
  • neuroscience
Date of Defense 2017-05-31
Availability unrestricted
Abstract
Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1, which encodes the neuronal glutamate/aspartate/cysteine transporter EAAT3/EAAC1. Despite this, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a new model of Slc1a1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in 1) locomotor activity, 2) stereotypy, and 3) immediate early gene induction in the dorsal striatum following amphetamine administration. Further, Slc1a1-STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This is accompanied by reduced D1 receptor binding in the dorsal striatum of Slc1a1-STOP mice. Slc1a1-STOP mice also exhibit reduced extracellular dopamine concentrations both at baseline and following amphetamine challenge in the dorsal striatum. Viral-mediated restoration of Slc1a1/EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine induced locomotion and stereotypy in Slc1a1-STOP mice, consistent with an impact of EAAT3 loss on pre-synaptic dopaminergic function. Collectively, these findings represent the first indication that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.
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