Kopelman, Jared
(2020)
The role of Slc1a1 in OCD-relevant behavior and associated neural activity.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Obsessive compulsive disorder (OCD) is a severe neuropsychiatric illness with a lifetime prevalence of 2-3%. While the causes of OCD are unknown, there is a significant genetic component in the etiology of the disorder. Multiple studies have identified association of polymorphism in SLC1A1 with OCD, with the most common polymorphism resulting in increased expression of the encoded protein, excitatory amino acid transporter-3 (EAAT3), the neuronal glutamate transporter. Subsequent studies in rodents have identified a potential role for Slc1a1/EAAT3 in OCD-relevant behavior. In this dissertation, I followed up on these studies first by investigating the effect of overexpressing Slc1a1 on OCD-relevant behaviors in mice. I found a significant effect of Slc1a1 overexpression on amphetamine-induced behaviors, but no effect on baseline grooming behavior or anxiety-like behavior. Slc1a1-overexpressing (OE) mice consistently showed potentiated hyperlocomotion in response to a low dose of amphetamine and potentiated stereotypy behavior in response to a high dose of amphetamine. This potentiated response to the high dose of amphetamine was associated with increased cFos expression in the ventromedial striatum. I then used an unbiased machine learning algorithm to cluster behaviors in Slc1a1-OE mice and controls following administration of low dose amphetamine, high dose amphetamine, or vehicle. I found that this approach was able to successfully identify amphetamine-induced behaviors that differed between Slc1a1-OE mice and controls and showed that the behavioral response to amphetamine is potentiated in Slc1a1-OE mice relative to controls. Using this automated scoring, I found that stereotypy behavior was positively correlated with the number of cFos positive D1-neurons in the ventral striatum and negatively correlated with the number of cFos positive D2-neurons in the dorsal striatum. In contrast, locomotor behavior was positively correlated with the number of cFos positive D2-neurons in the dorsal striatum, indicating that there may be distinct populations of cells that drive distinct amphetamine-induced behavioral response. Lastly, I tested the effect of genetic ablation of Slc1a1 or pharmacological inhibition of EAAT3 on OCD-relevant behaviors in Sapap3-KO mice. I found no significant effects of manipulating Slc1a1/EAAT3 on any of the behaviors tested. Together, these data point toward a role for Slc1a1/EAAT3 in abnormal repetitive behavior.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
21 September 2020 |
| Date Type: |
Publication |
| Defense Date: |
3 August 2020 |
| Approval Date: |
21 September 2020 |
| Submission Date: |
7 August 2020 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
152 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
OCD, Slc1a1, EAAT3, EAAC1, Glutamate transporter |
| Date Deposited: |
21 Sep 2020 15:40 |
| Last Modified: |
21 Sep 2022 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/39641 |
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