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

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          Significance

          Genetic linkage and association studies in obsessive-compulsive disorder (OCD) implicate SLC1A1 (encoding the neuronal glutamate transporter excitatory amino acid transporter 3, EAAT3), and neuroimaging studies demonstrate abnormal basal ganglia circuit function in OCD. However, no previous studies have investigated the role of EAAT3 in these circuits or tested its impact on repetitive behavior. Using a combined genetic and pharmacological challenge approach, we have demonstrated that ablated expression of EAAT3 diminishes basal ganglia-mediated repetitive behavior in mice. Targeted rescue of midbrain expression points to an impact of EAAT3 on dopaminergic neuron function, suggesting a model for synthesizing glutamate and dopamine effects on stereotypic behavior. These findings provide evidence that EAAT3 impacts basal ganglia-dependent repetitive behavior and suggest a potential target for drug development.

          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 D 1 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.

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          Author and article information

          Journal
          Proc Natl Acad Sci U S A
          Proc. Natl. Acad. Sci. U.S.A
          pnas
          pnas
          PNAS
          Proceedings of the National Academy of Sciences of the United States of America
          National Academy of Sciences
          0027-8424
          1091-6490
          30 May 2017
          15 May 2017
          : 114
          : 22
          : 5719-5724
          Affiliations
          [1] aDepartment of Pharmacology, Vanderbilt University Medical Center , Nashville, TN 37232;
          [2] b New York State Psychiatric Institute , New York, NY 10032;
          [3] cDepartment of Psychiatry, University of Pittsburgh , Pittsburgh, PA 15260;
          [4] dCenter for Neuroscience Program, University of Pittsburgh , Pittsburgh, PA 15260;
          [5] eCenter for the Neural Basis of Cognition, University of Pittsburgh , Pittsburgh, PA 15260;
          [6] fHoward Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital , Boston, MA 02114;
          [7] gCenter for Human Genetic Research, Massachusetts General Hospital , Boston, MA 02114;
          [8] hDepartment of Systems Biology, Harvard Medical School , Boston, MA 02115;
          [9] i Broad Institute , Cambridge, MA 02142;
          [10] jDepartment of Psychiatry, Columbia University Medical Center , New York, NY 10032;
          [11] kDivision of Integrative Neuroscience, New York State Psychiatric Institute , New York, NY10032;
          [12] lVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, TN 37232;
          [13] mDepartment of Psychiatry, Columbia University Medical Center , New York, NY 10032;
          [14] nSackler Institute for Developmental Psychobiology, Columbia University Medical Center , New York, NY 10032;
          [15] oDepartment of Anesthesiology, Columbia University Medical Center , New York, NY 10032;
          [16] pDivision of Molecular Therapeutics, New York State Psychiatric Institute , New York, NY 10032;
          [17] qDepartment of Biomedical Sciences, Florida State University College of Medicine , Tallahassee, FL 32304;
          [18] rDepartment of Neuropsychiatry, School of Medicine, Keio University , Tokyo 108-8345, Japan
          Author notes
          1To whom correspondence may be addressed. Email: veenstr@ 123456nyspi.columbia.edu or ahmarise@ 123456upmc.edu .

          Edited by Susan G. Amara, National Institutes of Health, Bethesda, MD, and approved April 17, 2017 (received for review February 1, 2017)

          Author contributions: I.D.Z., C.K.J., G.S., H.M., S.E.A., and J.V. designed research; I.D.Z., M.O.C., J.M.K., E.N.K., D.F., K.M.N., and M.B. performed research; C.K., G.S., K.F.T., and H.M. contributed new reagents/analytic tools; I.D.Z., M.O.C., H.M., S.E.A., and J.V. analyzed data; and I.D.Z., S.E.A., and J.V. wrote the paper.

          Author information
          http://orcid.org/0000-0002-6349-1076
          Article
          PMC5465902 PMC5465902 5465902 201701736
          10.1073/pnas.1701736114
          5465902
          28507136
          4131f234-48a3-47f3-879b-72fd5c711bf3
          History
          Page count
          Pages: 6
          Funding
          Funded by: HHS | NIH | National Institute of Mental Health (NIMH) 100000025
          Award ID: MH096200
          Funded by: Brain and Behavior Research Foundation 100000874
          Award ID: Young Investigator Grant
          Categories
          Biological Sciences
          Neuroscience

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

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