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.

Article and author information

Author details

  1. Susana Mingote

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

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

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

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

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

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

    Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5861-111X
  8. Ilana Zucker-Scharff

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

    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

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

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

    Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7632-0439
  13. Holly Moore

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

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

    Department of Psychiatry, Columbia University, New York, United States
    For correspondence
    sgr1@columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 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.

Reviewing Editor

  1. Sacha B Nelson, Brandeis University, United States

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.

Version history

  1. Received: April 6, 2017
  2. Accepted: July 6, 2017
  3. Accepted Manuscript published: July 13, 2017 (version 1)
  4. Version of Record published: September 14, 2017 (version 2)

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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  1. Susana Mingote
  2. Nao Chuhma
  3. Abigail Kalmbach
  4. Gretchen M Thomsen
  5. Yvonne Wang
  6. Andra Mihali
  7. Caroline E Sferrazza
  8. Ilana Zucker-Scharff
  9. Anna-Claire Siena
  10. Martha G Welch
  11. José Lizardi-Ortiz
  12. David Sulzer
  13. Holly Moore
  14. Inna Gaisler-Salomon
  15. Stephen Rayport
(2017)
Dopamine neuron dependent behaviorsmediated by glutamate cotransmission
eLife 6:e27566.
https://doi.org/10.7554/eLife.27566

Share this article

https://doi.org/10.7554/eLife.27566

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