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Dopamine neuron dependent behaviorsmediated by glutamate cotransmission

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Cite this article 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.

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.

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, 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)
  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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Further reading

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    Individuals with congenital amusia have a lifelong history of unreliable pitch processing. Accordingly, they downweight pitch cues during speech perception and instead rely on other dimensions such as duration. We investigated the neural basis for this strategy. During fMRI, individuals with amusia (N=15) and controls (N=15) read sentences where a comma indicated a grammatical phrase boundary. They then heard two sentences spoken that differed only in pitch and/or duration cues, and selected the best match for the written sentence. Prominent reductions in functional connectivity were detected in the amusia group, between left prefrontal language-related regions and right hemisphere pitch-related regions, which reflected the between-group differences in cue weights in the same groups of listeners. Connectivity differences between these regions were not present during a control task. Our results indicate that the reliability of perceptual dimensions is linked with functional connectivity between frontal and perceptual regions, and suggest a compensatory mechanism.