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Investigating the Role of Obsessive-Compulsive Disorder Candidate Gene SLC1A1 in Basal Ganglia and Repetitive Behavior

dc.creatorZike, Isaac Daniel
dc.description.abstractObsessive-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.
dc.titleInvestigating the Role of Obsessive-Compulsive Disorder Candidate Gene SLC1A1 in Basal Ganglia and Repetitive Behavior
dc.contributor.committeeMemberCarrie Jones
dc.contributor.committeeMemberJames Bodfish
dc.contributor.committeeMemberGregg Stanwood
dc.contributor.committeeMemberJeremy Veenstra-VanderWeele
dc.type.materialtext University
dc.contributor.committeeChairAriel Deutch

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