Supersensitive dopamine D2 receptor inhibition of the striatopallidal projection

纹状体多巴胺D2受体（D2 R）表达的中型棘神经元（D2-MSN）项目 苍白球（GP）中的GABA能神经元，形成基底神经节运动的重要环节 控制回路当D2-MSN发射尖峰时，它们的靶GP神经元被抑制。纹状体体轴突 终末表达抑制GABA释放的D2 R，从而减少GP神经元的抑制。在 帕金森病（PD），由于严重的多巴胺损失，这种D2 R介导的阴性对照在 纹状体锥体轴突终末减少或丢失。同时，多巴胺受体，包括D2 R， 作为稳态反应变得超敏感，甚至可能介导 多巴胺能治疗帕金森病然而，尽管它的重要性，D2 R超敏反应在纹状体， 轴突终末尚未被研究，其功能后果也仍然未知。这项建议 旨在填补这两个知识空白。 基于文献和我们的初步数据，我们假设：（1）突触前D2 Rs在 纹状体体轴突末梢在多巴胺耗竭后超敏，和（2）在 多巴胺能治疗后，超敏突触前D2 Rs解除了超敏突触后GP神经元的抑制。 方式我们将使用定量电生理学方法和2个小鼠模型来测试这些想法， 持续失去DA该项目的结果将确定突触前D2 R介导的对突触后神经元的抑制是否与突触前D2 R介导的对突触后神经元的抑制有关。 在DA耗尽（帕金森病）条件下，纹状体苍白球投射是超敏的。如果得到证实，这是一个 新的机制，可以弥补多巴胺的损失，在PD，和突触前D2 Rs上的 纹状体体轴突终末也可能是PD的多巴胺能治疗的靶点。

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.