Université de Bordeaux, Institut des Maladies Neurodégénératives, 33000 Bordeaux, France; CNRS UMR 5293, Institut des Maladies Neurodégénératives, 33000 Bordeaux, France.
Department of Pharmacology, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain.
Cell Rep. 2018 May 8;23(6):1678-1690. doi: 10.1016/j.celrep.2018.04.014.
The external globus pallidus (GP) is a key GABAergic hub in the basal ganglia (BG) circuitry, a neuronal network involved in motor control. In Parkinson's disease (PD), the rate and pattern of activity of GP neurons are profoundly altered and contribute to the motor symptoms of the disease. In rodent models of PD, the striato-pallidal pathway is hyperactive, and extracellular GABA concentrations are abnormally elevated in the GP, supporting the hypothesis of an alteration of neuronal and/or glial clearance of GABA. Here, we discovered the existence of persistent GABAergic tonic inhibition in GP neurons of dopamine-depleted (DD) rodent models. We showed that glial GAT-3 transporters are downregulated while neuronal GAT-1 function remains normal in DD rodents. Finally, we showed that blocking GAT-3 activity in vivo alters the motor coordination of control rodents, suggesting that GABAergic tonic inhibition in the GP contributes to the pathophysiology of PD.
外苍白球（GP）是基底神经节（BG）回路中 GABA 能中枢的关键组成部分，该神经元网络参与运动控制。在帕金森病（PD）中，GP 神经元的活动速率和模式发生了深刻改变，导致了疾病的运动症状。在 PD 的啮齿动物模型中，纹状体苍白球通路过度活跃，GP 中的细胞外 GABA 浓度异常升高，支持神经元和/或神经胶质细胞 GABA 清除能力改变的假说。在这里，我们发现多巴胺耗竭（DD）啮齿动物模型中存在持续的 GP 神经元 GABA 紧张性抑制。我们表明，在 DD 啮齿动物中，胶质 GABA 转运蛋白 GAT-3 下调，而神经元 GABA 转运蛋白 GAT-1 功能保持正常。最后，我们表明在体内阻断 GAT-3 活性会改变对照啮齿动物的运动协调性，这表明 GP 中的 GABA 紧张性抑制有助于 PD 的病理生理学。
