GABA co-released from striatal dopamine axons dampens phasic dopamine release through autoregulatory GABAA receptors

Jyoti C. Patel, Ang D. Sherpa, Riccardo Melani, Paul Witkovsky, Madeline R. Wiseman, Brian O'Neill, Chiye Aoki, Nicolas X. Tritsch, Margaret E. Rice

Research output: Contribution to journalArticlepeer-review

Abstract

Striatal dopamine axons co-release dopamine and gamma-aminobutyric acid (GABA), using GABA provided by uptake via GABA transporter-1 (GAT1). Functions of GABA co-release are poorly understood. We asked whether co-released GABA autoinhibits dopamine release via axonal GABA type A receptors (GABAARs), complementing established inhibition by dopamine acting at axonal D2 autoreceptors. We show that dopamine axons express α3-GABAAR subunits in mouse striatum. Enhanced dopamine release evoked by single-pulse optical stimulation in striatal slices with GABAAR antagonism confirms that an endogenous GABA tone limits dopamine release. Strikingly, an additional inhibitory component is seen when multiple pulses are used to mimic phasic axonal activity, revealing the role of GABAAR-mediated autoinhibition of dopamine release. This autoregulation is lost in conditional GAT1-knockout mice lacking GABA co-release. Given the faster kinetics of ionotropic GABAARs than G-protein-coupled D2 autoreceptors, our data reveal a mechanism whereby co-released GABA acts as a first responder to dampen phasic-to-tonic dopamine signaling.

Original languageEnglish (US)
Article number113834
JournalCell Reports
Volume43
Issue number3
DOIs
StatePublished - Mar 26 2024

Keywords

  • autoregulation
  • CP: Neuroscience
  • fast-scan cyclic voltammetry
  • GABA receptors
  • immuno-EM
  • immunohistochemistry
  • mice
  • optogenetic stimulation
  • phasic-to-tonic dopamine signaling
  • striatal slices
  • transmitter co-release

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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