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

Bradley M. Roberts (), Natalie M. Doig, Katherine R. Brimblecombe, Emanuel F. Lopes, Ruth E. Siddorn, Sarah Threlfell, Natalie Connor-Robson, Nora Bengoa-Vergniory, Nicholas Pasternack, Richard Wade-Martins, Peter J. Magill and Stephanie J. Cragg ()
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Bradley M. Roberts: University of Oxford
Natalie M. Doig: University of Oxford
Katherine R. Brimblecombe: University of Oxford
Emanuel F. Lopes: University of Oxford
Ruth E. Siddorn: University of Oxford
Sarah Threlfell: University of Oxford
Natalie Connor-Robson: University of Oxford
Nora Bengoa-Vergniory: University of Oxford
Nicholas Pasternack: University of Oxford
Richard Wade-Martins: University of Oxford
Peter J. Magill: University of Oxford
Stephanie J. Cragg: University of Oxford

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18247-5

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