dc.creator | Zike, Isaac Daniel | |
dc.date.accessioned | 2020-08-22T00:46:27Z | |
dc.date.available | 2017-05-26 | |
dc.date.issued | 2017-05-26 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-05232017-122303 | |
dc.identifier.uri | http://hdl.handle.net/1803/12373 | |
dc.description.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. | |
dc.format.mimetype | application/pdf | |
dc.subject | obsessive | |
dc.subject | compulsive | |
dc.subject | glutamate | |
dc.subject | neuroscience | |
dc.title | Investigating the Role of Obsessive-Compulsive Disorder Candidate Gene
SLC1A1 in Basal Ganglia and Repetitive Behavior | |
dc.type | dissertation | |
dc.contributor.committeeMember | Carrie Jones | |
dc.contributor.committeeMember | James Bodfish | |
dc.contributor.committeeMember | Gregg Stanwood | |
dc.contributor.committeeMember | Jeremy Veenstra-VanderWeele | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Pharmacology | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2017-05-26 | |
local.embargo.lift | 2017-05-26 | |
dc.contributor.committeeChair | Ariel Deutch | |