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      Behavioral and synaptic alterations relevant to obsessive-compulsive disorder in mice with increased EAAT3 expression

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          Abstract

          Obsessive-compulsive disorder (OCD) is a severe, chronic neuropsychiatric disorder with a strong genetic component. The SLC1A1 gene encoding the neuronal glutamate transporter EAAT3 has been proposed as a candidate gene for this disorder. Gene variants affecting SLC1A1 expression in human brain tissue have been associated with OCD. Several mouse models fully or partially lacking EAAT3 have shown no alterations in baseline anxiety-like or repetitive behaviors. We generated a transgenic mouse model (EAAT3 glo) to achieve conditional, Cre-dependent EAAT3 overexpression and evaluated the overall impact of increased EAAT3 expression at behavioral and synaptic levels. Mice with EAAT3 overexpression driven by CaMKIIα-promoter (EAAT3 glo/CMKII) displayed increased anxiety-like and repetitive behaviors that were both restored by chronic, but not acute, treatment with fluoxetine or clomipramine. EAAT3 glo/CMKII mice also displayed greater spontaneous recovery of conditioned fear. Electrophysiological and biochemical analyses at corticostriatal synapses of EAAT3 glo/CMKII mice revealed changes in NMDA receptor subunit composition and altered NMDA-dependent synaptic plasticity. By recapitulating relevant behavioral, neurophysiological, and psychopharmacological aspects, our results provide support for the glutamatergic hypothesis of OCD, particularly for the increased EAAT3 function, and provide a valuable animal model that may open novel therapeutic approaches to treat this devastating disorder.

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          Author and article information

          Contributors
          56-32-2995534 , andres.chavez@uv.cl
          56-32-2608463 , pablo.moya@uv.cl
          Journal
          Neuropsychopharmacology
          Neuropsychopharmacology
          Neuropsychopharmacology
          Springer International Publishing (Cham )
          0893-133X
          1740-634X
          26 December 2018
          May 2019
          : 44
          : 6
          : 1163-1173
          Affiliations
          [1 ] ISNI 0000 0000 8912 4050, GRID grid.412185.b, Instituto de Fisiología, Facultad de Ciencias, , Universidad de Valparaíso, ; Valparaíso, Chile
          [2 ] ISNI 0000 0000 8912 4050, GRID grid.412185.b, Núcleo Milenio NUMIND Biology of Neuropsychiatric Disorders, Facultad de Ciencias, , Universidad de Valparaíso, ; Valparaíso, Chile
          [3 ] ISNI 0000 0000 8912 4050, GRID grid.412185.b, Centro Interdisciplinario de Neurociencias de Valparaíso CINV, Facultad de Ciencias, , Universidad de Valparaíso, ; Valparaíso, Chile
          [4 ] ISNI 0000 0000 8912 4050, GRID grid.412185.b, Instituto de Neurociencias, Facultad de Ciencias, , Universidad de Valparaíso, ; Valparaíso, Chile
          [5 ] ISNI 0000 0004 0481 4802, GRID grid.420085.b, Laboratory of Behavioral and Genomic Neuroscience, , National Institute on Alcohol Abuse and Alcoholism, ; Rockville, MD USA
          [6 ] ISNI 0000 0001 2195 6763, GRID grid.259956.4, Department of Psychology and Center for Neuroscience and Behavior, , Miami University, ; Oxford, OH USA
          [7 ] ISNI 0000 0001 2205 0568, GRID grid.419633.a, Functional Genomics Section and Gene Transfer Core, , National Institute of Dental and Craniofacial Research, ; Bethesda, MD USA
          [8 ] ISNI 0000 0004 0385 4466, GRID grid.443909.3, Department of Biology, Faculty of Sciences, , Universidad de Chile, ; Santiago, Chile
          [9 ] ISNI 0000 0000 8912 4050, GRID grid.412185.b, Centro de Neurobiología y Fisiolopatogía Integrativa, Facultad de Ciencias, , Universidad de Valparaíso, ; Valparaíso, Chile
          [10 ] ISNI 0000 0004 0464 0574, GRID grid.416868.5, Laboratory of Clinical Science, , National Institute of Mental Health, ; Bethesda, MD USA
          [11 ]Present Address: Takeda Pharmaceutical Company Limited, 35 Landsdowne Street, Cambridge, MA 02139 USA
          Author information
          http://orcid.org/0000-0001-8114-023X
          http://orcid.org/0000-0002-8348-1799
          http://orcid.org/0000-0001-5106-5013
          http://orcid.org/0000-0001-8795-9238
          Article
          PMC6462043 PMC6462043 6462043 302
          10.1038/s41386-018-0302-7
          6462043
          30622300
          f289abaf-31ee-4ef8-94c6-f10865e4b767
          © American College of Neuropsychopharmacology 2019
          History
          : 2 August 2018
          : 1 December 2018
          : 15 December 2018
          Funding
          Funded by: FundRef https://doi.org/10.13039/501100005886, Ministerio de Economía, Fomento y Turismo (Ministry of Economy, Development and Tourism);
          Award ID: ICM P09-022F
          Award ID: ICM P09-022F
          Award Recipient :
          Funded by: FundRef https://doi.org/10.13039/100000072, U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIDCR);
          Award ID: Intramural Research Program
          Award Recipient :
          Funded by: FundRef https://doi.org/10.13039/100000027, U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAAA);
          Award ID: Intramural Research Program
          Award Recipient :
          Funded by: FundRef https://doi.org/10.13039/100000025, U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH);
          Award ID: Intramural Research Program
          Award Recipient :
          Funded by: FundRef https://doi.org/10.13039/501100002847, Ministerio de Educación, Gobierno de Chile (Ministry of Education, Government of Chile);
          Award ID: CONICYT 1141272
          Award Recipient :
          Categories
          Article
          Custom metadata
          © American College of Neuropsychopharmacology 2019

          Behavioural methods,Transporters in the nervous system,Genetic engineering,Electrophysiology

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