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OCD candidate gene /EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior.

Title: OCD candidate gene /EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior.
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Name(s): Zike, Isaac D, author
Chohan, Muhammad O, author
Kopelman, Jared M, author
Krasnow, Emily N, author
Flicker, Daniel, author
Nautiyal, Katherine M, author
Bubser, Michael, author
Kellendonk, Christoph, author
Jones, Carrie K, author
Stanwood, Gregg, author
Tanaka, Kenji Fransis, author
Moore, Holly, author
Ahmari, Susanne E, author
Veenstra-VanderWeele, Jeremy, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2017-05-30
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: 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 , which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of 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 () locomotor activity, () stereotypy, and () immediate early gene induction in the dorsal striatum following amphetamine administration. Further, -STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This reduced grooming is accompanied by reduced dopamine D receptor binding in the dorsal striatum of -STOP mice. -STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of /EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in -STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.
Identifier: FSU_pmch_28507136 (IID), 10.1073/pnas.1701736114 (DOI), PMC5465902 (PMCID), 28507136 (RID), 28507136 (EID), 1701736114 (PII)
Keywords: EAAC1, Tourette, Basal ganglia, Dopamine, Obsessive-compulsive disorder
Grant Number: R01 MH114296, R21 MH096200,
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465902.
Subject(s): Amphetamines/pharmacology
Animals
Basal Ganglia/physiology
Cell Line
Central Nervous System Stimulants/pharmacology
Dopamine/metabolism
Excitatory Amino Acid Transporter 3/genetics
Glutamic Acid/metabolism
Grooming/physiology
Maze Learning/physiology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Motor Activity/genetics
Motor Activity/physiology
Obsessive-Compulsive Disorder/genetics
Obsessive-Compulsive Disorder/physiopathology
Receptors, Dopamine D1/metabolism
Reflex, Startle/physiology
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_28507136
Owner Institution: FSU
Is Part Of: Proceedings of the National Academy of Sciences of the United States of America.
1091-6490
Issue: iss. 22, vol. 114

Choose the citation style.
Zike, I. D., Chohan, M. O., Kopelman, J. M., Krasnow, E. N., Flicker, D., Nautiyal, K. M., … Veenstra-VanderWeele, J. (2017). OCD candidate gene /EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior. Proceedings Of The National Academy Of Sciences Of The United States Of America. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_28507136