GABA Co-Released from Striatal Dopamine Axons Dampens Phasic Dopamine Release Through Autoregulatory GABA A Receptors
47 Pages Posted: 26 Oct 2022 Publication Status: Review CompleteMore...
Striatal dopamine axons co-release dopamine and gamma-aminobutyric acid (GABA), with GABA provided by uptake via GAT1 transporters. The function of GABA co-release remains unknown. We asked whether co-released GABA autoregulates dopamine release via axonal GABAA receptors (GABAARs), complementing established inhibition by dopamine acting at axonal D2 autoreceptors. We show that ~50% of 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, the functional role of GABAAR-mediated autoinhibition of dopamine release is revealed when multiple pulses are used to mimic phasic axonal activity. This autoregulatory component is lost in conditional GAT1-knockout mice lacking GABA corelease. Given the faster kinetics of ionotropic GABAARs than G-protein-coupled D2 autoreceptors, our data introduce a novel mechanism by which co-released GABA acts as a first responder to dampen phasic-to-tonic dopamine signaling.
Funding Information: Funding was provided by NIH grants R01DA038616 (M.E.R.) and DP2NS105553 (N.X.T.), the Attilio and Olympia Ricciardi Research Fund (M.E.R. and J.C.P.) and a Marlene and Paolo Fresco Postdoctoral Fellowship (R.M.).
Declaration of Interests: Brian O’Neill is currently employed at Addgene. All other authors declare no competing interests.
Ethics Approval Statement: All animal procedures were in accordance with NIH guidelines “Principles of Laboratory Animal Care” (NIH publication number 85-23) and were approved by the NYU Langone Health Animal Care and Use Committee. Efforts were made to minimize the number of animals used.
Keywords: mice, optogenetic stimulation, GABA co-release, phasic-to-tonic dopamine signaling
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