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Proc Natl Acad Sci U S A. 2017 May 30;114(22):5719-5724. doi: 10.1073/pnas.1701736114. Epub 2017 May 15.

OCD candidate gene SLC1A1/EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior.

Author information

1
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232.
2
New York State Psychiatric Institute, New York, NY 10032.
3
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15260.
4
Center for Neuroscience Program, University of Pittsburgh, Pittsburgh, PA 15260.
5
Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA 15260.
6
Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114.
7
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114.
8
Department of Systems Biology, Harvard Medical School, Boston, MA 02115.
9
Broad Institute, Cambridge, MA 02142.
10
Department of Psychiatry, Columbia University Medical Center, New York, NY 10032.
11
Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY10032.
12
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232.
13
Sackler Institute for Developmental Psychobiology, Columbia University Medical Center, New York, NY 10032.
14
Department of Anesthesiology, Columbia University Medical Center, New York, NY 10032.
15
Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032.
16
Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32304.
17
Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo 108-8345, Japan.
18
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15260; veenstr@nyspi.columbia.edu ahmarise@upmc.edu.
19
New York State Psychiatric Institute, New York, NY 10032; veenstr@nyspi.columbia.edu ahmarise@upmc.edu.

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 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 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 (i) locomotor activity, (ii) stereotypy, and (iii) 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 reduced grooming is accompanied by reduced dopamine D1 receptor binding in the dorsal striatum of Slc1a1-STOP mice. Slc1a1-STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. 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 presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.

KEYWORDS:

EAAC1; Tourette; basal ganglia; dopamine; obsessive-compulsive disorder

PMID:
28507136
PMCID:
PMC5465902
DOI:
10.1073/pnas.1701736114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: C.K. has received research funding from Forest. C.K.J. has received research funding from AstraZeneca, Johnson & Johnson, Bristol-Myers Squibb, and Seaside Therapeutics. J.V. has consulted or served on advisory boards for Roche, Novartis, and SynapDx and has received research funding from Roche, Novartis, SynapDx, Seaside Therapeutics, and Forest.

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