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Dopamine neuron dependent behaviorsmediated by glutamate cotransmission

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Cite as: eLife 2017;6:e27566 doi: 10.7554/eLife.27566

Abstract

Dopamine neurons in the ventral tegmental area use glutamate as a cotransmitter. To elucidate the behavioral role of the cotransmission, we targeted the glutamate-recycling enzyme glutaminase (gene Gls1). In mice with a dopamine transporter (Slc6a3)-driven conditional heterozygous (cHET) reduction of Gls1 in their dopamine neurons, dopamine neuron survival and transmission were unaffected, while glutamate cotransmission at phasic firing frequencies was reduced, enabling focusing the cotransmission. The mice showed normal emotional and motor behaviors, and an unaffected response to acute amphetamine. Strikingly, amphetamine sensitization was reduced and latent inhibition potentiated. These behavioral effects, also seen in global GLS1 HETs with a schizophrenia resilience phenotype, were not seen in mice with an Emx1-driven forebrain reduction affecting most brain glutamatergic neurons. Thus, a reduction in dopamine neuron glutamate cotransmission appears to mediate significant components of the GLS1 HET schizophrenia resilience phenotype, and glutamate cotransmission appears to be important in attribution of motivational salience.

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Author details

  1. Susana Mingote

    1. Department of Psychiatry, Columbia University, New York, United States
    For correspondence
    1. mingote@nyspi.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Nao Chuhma

    1. Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Abigail Kalmbach

    1. Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Gretchen M Thomsen

    1. Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yvonne Wang

    1. Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Andra Mihali

    1. Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Caroline E Sferrazza

    1. Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0001-5861-111X
  8. Ilana Zucker-Scharff

    1. Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Anna-Claire Siena

    1. Department of Molecular Therapeutics, NYS Psychiatric Institute, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Martha G Welch

    1. Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. José Lizardi-Ortiz

    1. Department of Neurology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. David Sulzer

    1. Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0001-7632-0439
  13. Holly Moore

    1. Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Inna Gaisler-Salomon

    1. Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Stephen Rayport

    1. Department of Psychiatry, Columbia University, New York, United States
    For correspondence
    1. sgr1@columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0001-9755-7486

Funding

National Institute on Drug Abuse (MH 087758)

  • Stephen Rayport

National Institute on Drug Abuse (DA017978)

  • Stephen Rayport

NARSAD (Young Investigator Award)

  • Susana Mingote

National Institute of Mental Health (MH086404)

  • Holly Moore
  • Stephen Rayport

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health, under protocols approved by the Institutional Animal Care and Use Committees of Columbia University (# AC-AAAB2862) and New York State Psychiatric Institute (# 1249). All surgery was performed under ketamine + xylazine anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Sacha B Nelson, Reviewing Editor, Brandeis University, United States

Publication history

  1. Received: April 6, 2017
  2. Accepted: July 6, 2017
  3. Accepted Manuscript published: July 13, 2017 (version 1)

Copyright

© 2017, Mingote et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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