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

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

doi:10.1038/s41467-020-18247-5

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.

Highlights

Striatal dopamine (DA) is critical for action and learning
We recently reported that axonal DA release in the dorsal striatum is under tonic inhibition by striatal GABA, as GABAA and GABAB receptor antagonists enhanced DA release evoked by single electrical and targeted optogenetic stimuli[3]
Since mechanisms that regulate striatal DA release can diverge between dorsal and ventral striatal territories[28,29,30,31,32,33], we first determined whether DA release in nucleus accumbens core (NAcC), within the ventral striatum, is regulated by tonic GABA inhibition

Summary

Introduction

Striatal dopamine (DA) is critical for action and learning. Recent data show that DA release is under tonic inhibition by striatal GABA. 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. We reveal firstly that GAT-1 and GAT-3 strongly regulate striatal DA release in the dorsolateral striatum (DLS) but not in the nucleus accumbens core (NAcC), by limiting tonic inhibition arising from striatal ambient GABA. We identify a role for GATs located on striatal astrocytes in supporting DA release, and we reveal maladaptive reductions in GAT levels that impair DA output in the DLS in a mouse model of early parkinsonism

Methods

Results

Conclusion