GABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model

Roberts, Bradley M., Doig, Natalie M., Brimblecombe, Katherine R., Lopes, Emanuel F., Siddorn, Ruth E., Threlfell, Sarah, Connor-Robson, Natalie ORCID: https://orcid.org/0000-0001-8350-6928, Bengoa-Vergniory, Nora, Pasternack, Nicholas, Wade-Martins, Richard, Magill, Peter J. and Cragg, Stephanie J. 2020. GABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model. Nature Communications 11 (1) , 4958. 10.1038/s41467-020-18247-5

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Abstract

Striatal dopamine (DA) is critical for action and learning. Recent data show that DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be determined by plasma membrane GABA uptake transporters (GATs) located on astrocytes and neurons. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs are downregulated, tonic GABAergic inhibition of DA release augmented, and nigrostriatal GABA co-release attenuated. These data define previously unappreciated and important roles for GATs and astrocytes in supporting DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	28 June 2021
Date of Acceptance:	13 August 2020
Last Modified:	16 May 2023 03:53
URI:	https://orca.cardiff.ac.uk/id/eprint/142157

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