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
Affiliations
Jyoti C. Patel
Department of Neurosurgery, New York University Grossman School of Medicine, 550 First Avenue, New York, NY 10016, USA; Corresponding author
Ang D. Sherpa
Department of Neurosurgery, New York University Grossman School of Medicine, 550 First Avenue, New York, NY 10016, USA; Center for Neural Science New York University, 4 Washington Place, New York, NY 10003, USA
Riccardo Melani
NYU Neuroscience Institute, New York University Grossman School of Medicine, 550 First Avenue, New York, NY 10016, USA
Paul Witkovsky
Department of Neurosurgery, New York University Grossman School of Medicine, 550 First Avenue, New York, NY 10016, USA
Madeline R. Wiseman
Department of Neurosurgery, New York University Grossman School of Medicine, 550 First Avenue, New York, NY 10016, USA
Brian O’Neill
Department of Neurosurgery, New York University Grossman School of Medicine, 550 First Avenue, New York, NY 10016, USA
Chiye Aoki
NYU Neuroscience Institute, New York University Grossman School of Medicine, 550 First Avenue, New York, NY 10016, USA; Center for Neural Science New York University, 4 Washington Place, New York, NY 10003, USA
Nicolas X. Tritsch
NYU Neuroscience Institute, New York University Grossman School of Medicine, 550 First Avenue, New York, NY 10016, USA
Margaret E. Rice
Department of Neurosurgery, New York University Grossman School of Medicine, 550 First Avenue, New York, NY 10016, USA; NYU Neuroscience Institute, New York University Grossman School of Medicine, 550 First Avenue, New York, NY 10016, USA; Corresponding author
Summary: 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.
