Supersensitive dopamine D2 receptor inhibition of the striatopallidal projection

描述（由申请人提供）：纹状体中表达多巴胺D2受体（D2 R）的中型多棘神经元（D2-MSN）投射到苍白球（GP）中的GABA能神经元，形成基底神经节运动控制回路中的重要环节。当D2-MSN发射尖峰时，它们的靶GP神经元被抑制。纹状体苍白球轴突终末表达D2 Rs，其抑制GABA释放，从而减少GP神经元的抑制。在帕金森氏病（PD）中，由于严重的多巴胺损失，这种D2 R介导的阴性控制在纹状体体轴突终末减少或丢失。同时，包括D2 R在内的多巴胺受体作为稳态反应变得超敏感，甚至可能介导多巴胺能治疗PD的治疗效果。然而，尽管其重要性，D2 R超敏性在striatopallidal轴突终端尚未研究和功能的后果也仍然未知。本建议旨在填补这两个知识空白。 基于文献和我们的试验数据，我们假设：（1）多巴胺耗竭后，纹状体苍白球轴突终末的突触前D2 Rs超敏，（2）在多巴胺能治疗期间，超敏的突触前D2 Rs以超敏的方式抑制GP神经元。我们将使用定量电生理学方法和2个具有一致DA损失的小鼠模型来测试这些想法。本项目的结果将确定突触前D2 R介导的抑制纹状体投射是否在DA耗尽（帕金森病）条件下超敏。如果证实，这是一个新的机制，可以补偿PD的多巴胺的损失，和突触前D2 Rs上的纹状体体轴突终末也可能是一个目标的多巴胺能治疗PD。

DESCRIPTION (provided by applicant): The dopamine D2 receptor (D2R)-expressing medium spiny neurons (D2-MSN) in the striatum project to the GABAergic neurons in the globus pallidus (GP), forming an important link in the basal ganglia motor control circuit. When D2-MSNs fire spikes, their target GP neurons are inhibited. The striatopallidal axon terminals express D2Rs that inhibit GABA release and thus reduce the inhibition of GP neurons. In Parkinson's disease (PD), due to the severe dopamine loss, this D2R-mediated negative control at the striatopallidal axon terminals is reduced or lost. At the same time, dopamine receptors including D2Rs become supersensitive as a homeostatic response and may even mediate the therapeutic effects of dopaminergic treatments for PD. However, despite its importance, D2R supersensitivity at the striatopallidal axon terminals has not been studied and the functional consequences also remain unknown. This proposal is aimed at filling these two knowledge gaps. Based on the literature and our pilot data, we hypothesize that (1) presynaptic D2Rs at the striatopallidal axon terminals are supersensitized following dopamine depletion, and (2) during dopaminergic treatment, the supersensitive presynaptic D2Rs disinhibit GP neurons in a supersensitive manner. We will test these ideas using quantitative electrophysiological methods and 2 mouse models with consistent DA loss. Results from this project will determine if the presynaptic D2R-mediated inhibition of the striatopallidal projection is supersensitized under a DA-depleted (parkinsonian) condition. If proven, this is a new mechanism that can compensate for the loss of dopamine in PD, and the presynaptic D2Rs on the striatopallidal axon terminals may also be a target of the dopaminergic treatments for PD.