Supersensitive dopamine D2 receptor inhibition of the striatopallidal projection

纹状体投射中表达多巴胺D2受体的中棘神经元(D2-MSN) 至苍白球内的GABA能神经元，构成基底节运动的重要环节 控制电路。当D2-MSN发出尖峰时，它们的目标GP神经元受到抑制。纹状体前额叶轴突 终末表达D2Rs，抑制GABA的释放，从而减轻对GP神经元的抑制。在……里面 帕金森病(PD)，由于严重的多巴胺丢失，这种D2R介导的阴性对照在 纹状体皮质轴突终末减少或消失。同时，包括D2Rs在内的多巴胺受体 作为一种动态平衡反应而变得超敏感，甚至可能介导了 帕金森病的多巴胺能治疗。然而，尽管D2R很重要，纹状体的D2R超敏反应 轴突终末尚未被研究，其功能后果也尚不清楚。这项建议 旨在填补这两个知识空白。 根据文献和我们的实验数据，我们假设(1)突触前D2Rs在 纹状体苍白球轴突终末在多巴胺耗竭后超敏感，以及(2)在 多巴胺能处理后，超敏突触前D2Rs对GP神经元的抑制作用 举止。我们将使用定量电生理学方法和两个小鼠模型来测试这些想法 一致的地区检察官损失。该项目的结果将确定突触前D2R介导的抑制 纹状体丘脑的投射在多巴胺缺乏(帕金森氏症)的情况下是超敏感的。如果得到证实，这是一种 一种新的机制，可以补偿帕金森病患者多巴胺的丢失，以及突触前D2Rs在 纹状体皮质轴突终末也可能是多巴胺能治疗帕金森病的靶点。

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.