• A Correction to this article was published on 21 February 2019

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 (EAAT3glo) 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 (EAAT3glo/CMKII) displayed increased anxiety-like and repetitive behaviors that were both restored by chronic, but not acute, treatment with fluoxetine or clomipramine. EAAT3glo/CMKII mice also displayed greater spontaneous recovery of conditioned fear. Electrophysiological and biochemical analyses at corticostriatal synapses of EAAT3glo/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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Change history

  • 21 February 2019

    The original version of this Article contained an error in the spelling of the author Anna K Radke, which was incorrectly given as Anna R Radke. This has now been corrected in both the PDF and HTML versions of the Article.

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Acknowledgements

The authors especially thank Dr. Carla Alvarez and Pedro Espinosa for their work that forms the basis for Figures 4 and 5.

Author information

Author notes

    • Jens R. Wendland

    Present address: Takeda Pharmaceutical Company Limited, 35 Landsdowne Street, Cambridge, MA, 02139, USA

  1. These authors contributed equally: Claudia Delgado-Acevedo, Sebastián F. Estay.

  2. Dr. Dennis L. Murphy passed away on September 23, 2017.

Affiliations

  1. Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile

    • Claudia Delgado-Acevedo
    • , Angélica P. Escobar
    • , Francisca Henríquez-Belmar
    • , Cristopher A. Reyes
    • , Valentina Haro-Acuña
    • , Ramón Sotomayor-Zárate
    •  & Pablo R. Moya
  2. Núcleo Milenio NUMIND Biology of Neuropsychiatric Disorders, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile

    • Claudia Delgado-Acevedo
    • , Sebastián F. Estay
    • , Francisca Henríquez-Belmar
    • , Cristopher A. Reyes
    • , Valentina Haro-Acuña
    • , Andrés E. Chávez
    •  & Pablo R. Moya
  3. Centro Interdisciplinario de Neurociencias de Valparaíso CINV, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile

    • Claudia Delgado-Acevedo
    • , Sebastián F. Estay
    • , Angélica P. Escobar
    • , Andrés E. Chávez
    •  & Pablo R. Moya
  4. Instituto de Neurociencias, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile

    • Sebastián F. Estay
    •  & Andrés E. Chávez
  5. Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA

    • Anna K. Radke
    • , Ayesha Sengupta
    •  & Andrew Holmes
  6. Department of Psychology and Center for Neuroscience and Behavior, Miami University, Oxford, OH, USA

    • Anna K. Radke
  7. Functional Genomics Section and Gene Transfer Core, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA

    • Elías Utreras
    • , Andrew Cho
    •  & Ashok B. Kulkarni
  8. Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago, Chile

    • Elías Utreras
  9. Centro de Neurobiología y Fisiolopatogía Integrativa, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile

    • Ramón Sotomayor-Zárate
  10. Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD, USA

    • Jens R. Wendland
    • , Dennis L. Murphy
    •  & Pablo R. Moya

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