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

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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.

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Nicolas X Tritsch

Howard Hughes Medical Institute, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Won-Jong Oh

Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Chenghua Gu

Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.
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).

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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.