NMDA受体是调控黑质多巴胺（DA）能神经元簇状放电活动的关键因素之一，其受体亚型在突触后膜的分布突触内以NR2A为主，突触外以NR2B为主，两者的分布受非受体型酪氨酸激酶Fyn的调控。帕金森病（PD）患者和动物模型中黑质DA能神经元簇状放电增加，但机制不明。在本课题前期预实验中，给予NMDA受体阻断剂后，PD模型小鼠黑质DA能神经元簇状放电频率明显降低。为了阐明PD黑质DA能神经元NMDA受体亚型分布的改变与簇状放电的关系，以及Fyn对NMDA受体亚型分布的调控机制，本课题拟利用免疫电镜和在体细胞外记录等技术，在PD转基因动物模型上，观察NMDA受体亚型在突触部位的精细分布及其对黑质DA能神经元簇状放电活动的影响；并进一步探究Fyn调控DA能神经元NMDA受体亚型突触内外分布的分子机制。本研究将为NMDA受体参与PD的发病机制和作为潜在临床药物靶点提供实验依据。

NMDA receptor is one of the key factors that regulate the burst firing activity of dopaminergic (DAergic) neurons in substantia nigra. NR2A is mainly located at the synaptic site, whereas NR2B is mainly outside the synapses. Both two subtypes are involved in the control of the discharge activity of nigral DA neurons while their distribution is regulated by the non-receptor tyrosine kinase Fyn. The burst firing frequency of DAergic-neurons in the substantia nigra of Parkinson's disease (PD) increases. However, its underlying mechanism is unclear. Our preliminary study has found that the burst firing frequency of DAergic neurons in the substantia nigra of mice with PD is decreased significantly after administration of NMDA receptor blocker. In order to elucidate the relationship between distribution of NMDA receptor subtypes at synaptic site of DAergic neurons in substantia nigra and burst firing, and the regulatory mechanism of Fyn on the distribution of NMDA receptor subtypes in PD. In this study, we will observe the distribution of NMDA receptor subtypes at synaptic site and effects on burst firing activity of DA neurons in substantia nigra in PD transgenic animals by using techniques such as immunoelectron microscopy and extracellular recording. Furthermore, we will investigate the mechanism that how Fyn regulates the distribution of NMDA receptor subtypes, which will provide the correlation with burst firing frequency of DA neurons. This project will provide important experimental evidence for the mechanism underlying the involvement of NMDA receptor in PD pathogenesis and for the selection of NMDA receptor as new potential drug targets in PD.