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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 Complete

See all articles by Jyoti Patel

Jyoti Patel

New York University (NYU), School of Medicine, Langone Health Center, Laura and Isaac Perlmutter Cancer Center, Department of Neurosurgery

Ang D. Sherpa

New York University (NYU), School of Medicine, Langone Health Center, Laura and Isaac Perlmutter Cancer Center, Department of Neurosurgery

Riccardo Melani

New York University (NYU) - Neuroscience Institute

Brian O’Neill

New York University (NYU), School of Medicine, Langone Health Center, Laura and Isaac Perlmutter Cancer Center, Department of Neurosurgery

Nicolas X. Tritsch

New York University (NYU) - Neuroscience Institute

Chiye Aoki

New York University (NYU) - Neuroscience Institute

Margaret E. Rice

New York University (NYU), School of Medicine, Langone Health Center, Laura and Isaac Perlmutter Cancer Center, Department of Neurosurgery

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Abstract

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

Suggested Citation

Patel, Jyoti and Sherpa, Ang D. and Melani, Riccardo and O’Neill, Brian and Tritsch, Nicolas X. and Aoki, Chiye and Rice, Margaret E., GABA Co-Released from Striatal Dopamine Axons Dampens Phasic Dopamine Release Through Autoregulatory GABA A Receptors. Available at SSRN: https://ssrn.com/abstract=4246393 or http://dx.doi.org/10.2139/ssrn.4246393
This version of the paper has not been formally peer reviewed.

Jyoti Patel

New York University (NYU), School of Medicine, Langone Health Center, Laura and Isaac Perlmutter Cancer Center, Department of Neurosurgery

Ang D. Sherpa

New York University (NYU), School of Medicine, Langone Health Center, Laura and Isaac Perlmutter Cancer Center, Department of Neurosurgery ( email )

Riccardo Melani

New York University (NYU) - Neuroscience Institute ( email )

Brian O’Neill

New York University (NYU), School of Medicine, Langone Health Center, Laura and Isaac Perlmutter Cancer Center, Department of Neurosurgery ( email )

Nicolas X. Tritsch

New York University (NYU) - Neuroscience Institute ( email )

Chiye Aoki

New York University (NYU) - Neuroscience Institute ( email )

Margaret E. Rice (Contact Author)

New York University (NYU), School of Medicine, Langone Health Center, Laura and Isaac Perlmutter Cancer Center, Department of Neurosurgery ( email )

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