皮质纹状体代谢型谷氨酸受体2/3( mGluR2/3)调控晚期帕金森病猴异动症发生的机制

Pathological corticostriatal gulutamatergic synaptic plasticity is crucial in the development of LID（L-DOPA-induced dyskinesia）and modulation of glutamate receptor is the new therapeutic target for LID. Decreased expression of metabotropic glutamate receptor (mGluR2/3) in the dorsal striatum of LID rat models, and abnormal firing frequency and patterns of striatal medium spiny neurons (MSNs) in striatum slice patch clamp and MPTP-induced parkinsonian primates with dyskinesia were found in our previous study. The aims of this research are to investigate the amelioration of positive allosteric modulator (PAM) of mGluR2/3 on parkinsonian primates with dyskinesia, and explore the modulated effect of mGluR2/3 PAM on glutamatergic and GABAergic synaptic plasticity and firing activities in the striatal MSNs, and explain the mechanism of LID with the angles of electrophysiology and molecular biology, and provide a new therapeutic strategy for motor complications of Parkinson’s disease.

病理性皮质纹状体谷氨酸能突触可塑性在LID发生中至关重要，对谷氨酸受体的调控是LID治疗新的靶点。我们研究发现LID大鼠背侧纹状体代谢型谷氨酸受体mGluR2/3表达减少，同时在纹状体脑片膜片钳和MPTP诱导的晚期猴LID模型中发现纹状体MSNs存在放电频率和形式的异常改变。本课题拟通过研究II型代谢型谷氨酸受体(mGluR2/3)正相变构调节剂(PAM)对晚期帕金森病猴模型LID的改善作用, 探索mGluR2/3 PAM对NMDAR、AMPAR及GABA能神经元可塑性和在体纹状体MSNs电活动的调控，以期从电生理学和分子生物学多视角阐述LID的发病机制，为PD晚期运动并发症提供新的治疗策略。

本项目模拟左旋多巴诱发异动症（LID）的发病过程，从行为学、免疫组织化学、分子生物学和电生理等多个方面深入研究了LID发生、发展的详细机制，进一步确信了我们提出的“谷氨酸受体是LID治疗新的靶点”的观点。通过对mGluR2/3受体活性的调节，我们研究了其对LID的改善作用，探索了mGluR2/3配体对NMDAR及D1R下游信号通路的调控、对纹状体-初级运动皮层投射神经元电活动的调控，这为PD晚期运动并发症的治疗和预防提供了新的治疗思路。