GABA 摄取转运体支持背侧纹状体中的多巴胺释放，在帕金森病模型中适应性下调。

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

机构信息

Centre for Integrative Neuroscience, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.

Oxford Parkinson's Disease Centre, University of Oxford, Oxford, OX1 3PT, UK.

出版信息

Nat Commun. 2020 Oct 2;11(1):4958. doi: 10.1038/s41467-020-18247-5.

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.

纹状体多巴胺（DA）对运动和学习至关重要。最近的数据表明，DA 的释放受到纹状体 GABA 的紧张性抑制。位于星形胶质细胞和神经元上的细胞外膜 GABA 摄取转运体（GATs）可以决定纹状体投射神经元上的纹状体 GABA 紧张性。然而，纹状体 GATs 和星形胶质细胞是否决定 DA 的输出尚不清楚。我们揭示，小鼠背外侧纹状体而非伏隔核核心的 DA 释放受 GAT-1 和 GAT-3 调控。这些 GAT 部分定位于星形胶质细胞，与伏隔核核心相比，在背外侧纹状体中富集。在帕金森病早期的小鼠模型中，GAT 下调，DA 释放的紧张性 GABA 抑制增强，黑质纹状体 GABA 共释放减弱。这些数据定义了 GAT 和星形胶质细胞在支持纹状体 DA 释放中的以前未被认识到的重要作用，并揭示了早期帕金森病中的一种适应性不良的可塑性，损害了易损纹状体区域的 DA 输出。