Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis

  1. Nicolas X Tritsch
  2. Won-Jong Oh
  3. Chenghua Gu
  4. Bernardo L Sabatini  Is a corresponding author
  1. Howard Hughes Medical Institute, Harvard Medical School, United States
  2. Harvard Medical School, United States

Abstract

Synaptic transmission between midbrain dopamine neurons and target neurons in the striatum is essential for the selection and reinforcement of movements. Recent evidence indicates that nigrostriatal dopamine neurons inhibit striatal projection neurons by releasing a neurotransmitter that activates GABAA receptors. Here we demonstrate that this phenomenon extends to mesolimbic afferents, and confirm that the released neurotransmitter is GABA. However, the GABA synthetic enzymes GAD65 and GAD67 are not detected in midbrain dopamine neurons. Instead, these cells express the membrane GABA transporters mGAT1 (Slc6a1) and mGAT4 (Slc6a11) and inhibition of these transporters prevents GABA co-release. These findings therefore indicate that GABA co-release is a general feature of midbrain dopaminergic neurons that relies on GABA uptake from the extracellular milieu as opposed to de novo synthesis. This atypical mechanism may confer dopaminergic neurons the flexibility to differentially control GABAergic transmission in a target-dependent manner across their extensive axonal arbors.

Article and author information

Author details

  1. Nicolas X Tritsch

    Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Won-Jong Oh

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Chenghua Gu

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Bernardo L Sabatini

    Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    For correspondence
    bsabatini@hms.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

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. All experimental manipulations were performed in accordance with protocols approved by the Harvard Medical Area Standing Committee on Animal Care (#03551).

Reviewing Editor

  1. Gary L Westbrook, Vollum Institute, United States

Publication history

  1. Received: November 22, 2013
  2. Accepted: March 25, 2014
  3. Accepted Manuscript published: April 24, 2014 (version 1)
  4. Version of Record published: April 29, 2014 (version 2)

Copyright

© 2014, Tritsch et al.

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

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  1. Nicolas X Tritsch
  2. Won-Jong Oh
  3. Chenghua Gu
  4. Bernardo L Sabatini
(2014)
Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis
eLife 3:e01936.
https://doi.org/10.7554/eLife.01936

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