糖原合酶激酶 3 对树突棘可塑性的调控作用和机制及其应用

树突棘是位于神经元树突分支上的棘状突起，是重要的突触后组分，其可塑性的调节机制受到国内外学者的广泛关注。糖原合酶激酶3（GSK-3）在学习记忆中发挥重要的作用，但其对树突棘可塑性的调节尚不清楚。基于前期报道和申请者近期实验结果，本项目拟采用高尔基染色、胚胎电转等技术，利用已经成功引进的GSK-3敲除小鼠，结合荧光实时追踪等新兴技术辅以表观遗传学、慢病毒感染等分子生物学手段研究GSK-3对树突棘可塑性的调控作用和机制；最后，利用基因鼠杂交、穿透性多肽给药等手段，下调阿尔茨海默病（AD）模型小鼠脑内的GSK-3，观察是否可以逆转AD样的树突棘病变。该项目不仅可以进一步揭示GSK-3在神经元结构和功能中的作用，还可为AD早期认知功能障碍的治疗提供实验理论依据。

Dendritic spines are small protrusion in the dendritic branches in the neuron. They are the most important postsynaptic compartment and their regulation are highly focused by neuroscientists. Glycogen synthase kinase 3 plays an important role in the learning/memory but its role in dendritic spine plasticity is not clear. Based on previous reports and our recently results, we will explore the possible role and the underlying mechanisms of GSK-3 in dendritc spine plasticity by Golgi staining, in utero electroporation, time-lapse tracking and epigenetic and other molecular biological techniques. We will also apply transgenic mice crossing, permeable peptide deliver to examine whether downregulation of GSK-3 in Alzheimer's animal model could reverse the spine pathology in those mice. Our proposal will not only reveal the basic role of GSK-3 in neuronal function and structure, but also provide experimental evidences for the therapy of memory deficits in early AD patients.