帕金森病异动症发生中mBDNF-TrKB/proBDNF-p75NTR通路参与皮质-纹状体突触功能调控

Levodopa-induced dyskinesia(LID) severely impacts life quality in Parkinson’s disease(PD) patients, but there are a lot of unknown field about LID need to be done. The previous research mainly focus on the receptor functions and its signal transduction in the striatum，while little was known about the regulation of the inputs from cortical and thalamic to striatal MSNs. In our preliminary experiment, we found that in 6-OHDA-lesioned dyskinesia rats, cortical TrkB-FL receptor reduced significantly with the mature BDNF(mBDNF) remain the same while compared with the sham group and PD group. In the striatum, mBDNF and the TrkB-FL receptor decreased while compared with the PD and sham group. Furthermore, the expression level of the NMDA receptor subtype GluR1 and GluR2B were enhanced on the MSN membrane in striatum, in which, there is an increase in the interaction between the GluR1 and D1 receptor. All these data demonstrated that the mBDNF-TrkB signaling from the motor cortex might contribute to the development of LID via regulate the synaptic function of corticostriatal glutamic afferent. In this study, we intend to explore the function of the mBDNF-TrkB and proBDNF-p75NTR pathway in the corticostriatal and thalamostriatal radiation in the LID rats. Then we will also detect the alterations of the synaptic structure and function in the direct and indirect pathway. We will use thelevodopa/benserazide microsphere to treat the LID rats, explore the alterations in corticostriatal and thalamostriatal projection, in the purpose to elucidate the impact that the alteractions exert on the development of LID.

左旋多巴诱发的异动症（LID）严重影响帕金森病患者生活质量，其机制不明。以往研究多集中在纹状体的受体和信号转导，对皮层和丘脑调控纹状体投射神经元功能的研究甚少。我们前期研究发现LID大鼠运动皮质成熟型BDNF（mBDNF）无改变、TrkB-FL受体显著下调，而纹状体mBDNF减少、TrkB-FL受体表达降低；NMDA受体亚基GluR1/GluR2B在纹状体细胞膜上表达增多，其中GluR1与D1受体结合增多，GluR2B与mGluR5受体结合增多，提示运动皮质mBDNF-TrkB通路对纹状体谷氨酸能投射神经元突触功能的调节可能参与了LID发生。本课题拟研究LID鼠皮质和丘脑-纹状体mBDNF-TrkB/ proBDNF-p75NTR通路功能及对直接、间接通路投射神经元突触结构、功能的影响。利用我们前期研发的左旋多巴缓释微球处理LID鼠，探究皮层和丘脑-纹状体调控功能改变在LID发生中的作用。

帕金森病（PD）长期左旋多巴治疗产生运动并发症，其中异动症（LIDs）严重影响 患者的生活质量，其发生机制尚不明确。p75神经营养因子受体（p75NTR）在LID发生中的表达及作用未知。我们前期研究发现LID大鼠纹状体p75NTR水平明显升高，选择性敲低纹状体p75NTR或者利用免疫抑制剂下调p75NTR可产生抗异动症作用。本课题拟通过研究异动症p75NTR的水平、细胞定位以及p75NTR相关的ROCK2-LIMK1-Cofilin信号通路变化以及树突棘结构变化，解释p75NTR参与LID的作用及机制，为异动症提供新型的治疗靶点。