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

Elife. 2014 Apr 24;3:e01936. doi: 10.7554/eLife.01936.

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.DOI: http://dx.doi.org/10.7554/eLife.01936.001.

Keywords: GABA; GAT; basal ganglia; co-release; dopamine; striatum.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport
  • Corpus Striatum / cytology
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism*
  • GABA Agents / pharmacology
  • GABA Plasma Membrane Transport Proteins / metabolism
  • Inhibitory Postsynaptic Potentials
  • Mesencephalon / cytology
  • Mesencephalon / drug effects
  • Mesencephalon / metabolism*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neural Inhibition* / drug effects
  • Synapses / drug effects
  • Synapses / metabolism*
  • Synaptic Transmission* / drug effects
  • Time Factors
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • GABA Agents
  • GABA Plasma Membrane Transport Proteins
  • Slc6a1 protein, mouse
  • Slc6a11 protein, mouse
  • gamma-Aminobutyric Acid