大麻素调控中枢神经突触传递及可塑性的突触前细胞机制研究

成瘾性药物主要通过调控中枢神经突触传递的强度和时程获得兴奋和成瘾效果，对其调控机制的研究具有重要的社会和生物学意义。突触作为神经网络结构和功能的基本单元，是主要的神经信号联系方式。内源性大麻素在突触后合成，并逆行与突触前受体结合，直接调控突触传递及可塑性，但其在突触前的精细调控动力学和内在机制并不清楚。申请人前期研究发现，大麻素可以抑制突触前钙电流和囊泡的释放和回收，并与神经营养因子存在相互调控，显示大麻素具有重要的突触前调控作用。本课题以大麻素受体1（CB1R）条件敲除小鼠为标本，在脑干花萼状突触和原代海马培养神经元上，利用高精度膜电容膜片钳和荧光质粒标记技术，研究大麻素及其受体对突触传递及可塑性的精细动力学调控，探索其与神经营养因子相互作用的信号通路，并阐明其内在的分子细胞机制。本课题的研究成果将为大麻素及其受体调控神经信号传递提供新的认识，并为相关神经疾病的临床诊疗提供有价值的参考。

Addictive drugs mainly achieve their effects by regulating synaptic strength in the central nervous system. The underlying mechanism is one of the hotspots in current neuroscience with both social and biological significance. Chemical synaptic transmission, which serves as the primary link between neurons, is the fundamental building block of the neural network. Endocannabinoids are synthesized at the postsynaptic neurons and bind to the presynaptic receptors to modulate synaptic transmission and plasticity. However, the precise kinetics and the underlying mechanisms remain elusive. We have shown that endocannabinoids can inhibit the presynaptic calcium current and vesicle exo-endocytosis at the nerve terminal, indicating an essential presynaptic regulation in synaptic transmission. This project will combine high temporal resolution patch clamp of capacitance measurements and fluorescent imaging at the calyces and cultured hippocampal neurons in both wild-type and CB1R conditional knock out mice to study the precise regulation of endocannabinoid modulated synaptic transmission and plasticity, and explore the underlying mechanism. We will also investigate the signaling cascade between endocannabinoid and the neurotrophic factors to unfold their interaction. This study will shed light on the endocannabinoid/CB1R-modulated neuronal signaling cascade, and provide new insights into the treatments of related neurological diseases.