Roundabout receptor 2 maintains inhibitory control of the adult midbrain

  1. Bryan B Gore
  2. Samara M Miller
  3. Yong Sang Jo
  4. Madison Baird
  5. Mrinalini Hoon
  6. Christina A Sanford
  7. Avery Hunker
  8. Weining Lu
  9. Rachel O Wong
  10. Larry S Zweifel  Is a corresponding author
  1. University of Washington, United Kingdom
  2. University of Washington, United States
  3. Boston University Medical Center, United States

Abstract

The maintenance of excitatory and inhibitory balance in the brain is essential for its function. Here we find that the developmental axon guidance receptor Roundabout 2 (Robo2) is critical for the maintenance of inhibitory synapses in the adult ventral tegmental area (VTA), a brain region important for the production of the neurotransmitter dopamine. Following selective genetic inactivation of Robo2 in the adult VTA of mice, reduced inhibitory control results in altered neural activity patterns, enhanced phasic dopamine release, behavioral hyperactivity, associative learning deficits, and a paradoxical inversion of psychostimulant responses. These behavioral phenotypes could be phenocopied by selective inactivation of synaptic transmission from local GABAergic neurons of the VTA, demonstrating an important function for Robo2 in regulating the excitatory and inhibitory balance of the adult brain.

Article and author information

Author details

  1. Bryan B Gore

    Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Samara M Miller

    Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yong Sang Jo

    Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Madison Baird

    Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Mrinalini Hoon

    Department of Biological Structure, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Christina A Sanford

    Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Avery Hunker

    Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Weining Lu

    Department of Medicine, Boston University Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Rachel O Wong

    Department of Biological Structure, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Larry S Zweifel

    Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, United States
    For correspondence
    larryz@uw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3465-5331

Funding

National Institutes of Health (R01-MH094536)

  • Larry S Zweifel

National Institute for Health Research (EY10699)

  • Rachel O Wong

National Institute for Health Research (R01-DK078226)

  • Weining Lu

National Institutes of Health (R01-MH104450)

  • Larry S Zweifel

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

Ethics

Animal experimentation: All experiments were done in accordance with a protocol (4249-01) approved by the University of Washington Animal Care and Use Committee.

Reviewing Editor

  1. Eunjoon Kim, Institute for Basic Science, Korea Advanced Institute of Science and Technology, Korea (South), Republic of

Publication history

  1. Received: December 2, 2016
  2. Accepted: April 9, 2017
  3. Accepted Manuscript published: April 10, 2017 (version 1)
  4. Version of Record published: May 5, 2017 (version 2)

Copyright

© 2017, Gore 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. Bryan B Gore
  2. Samara M Miller
  3. Yong Sang Jo
  4. Madison Baird
  5. Mrinalini Hoon
  6. Christina A Sanford
  7. Avery Hunker
  8. Weining Lu
  9. Rachel O Wong
  10. Larry S Zweifel
(2017)
Roundabout receptor 2 maintains inhibitory control of the adult midbrain
eLife 6:e23858.
https://doi.org/10.7554/eLife.23858
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