七氟醚暴露经NMDAR-GSK3β-Tau通路影响发育中大脑突触可塑性的研究

项目名称： 七氟醚暴露经NMDAR-GSK3β-Tau通路影响发育中大脑突触可塑性的研究

项目编号： No.81471240

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 胡智勇

作者单位： 浙江大学

项目金额： 70万元

中文摘要： 七氟醚对发育中大脑的神经毒性日益受到关注。实验证实七氟醚可导致神经元凋亡、学习记忆功能障碍，幼年暴露甚至可影响人成年后的认知能力和精神行为，但其机制迄今未明。我们前期研究发现七氟醚可引起海马微管结构紊乱、Tau蛋白过度磷酸化及抑制兴奋性突触后电位等。在此基础上本课题拟首先探明未成熟大脑七氟醚暴露对海马LTP/LTD的近、远期影响；阐明其通过调控NMDA受体亚基NR2A/B功能、组成及空间分布使GSK3β-Tau通路活性增强，从而影响海马突触可塑性和再可塑性的机制；进一步拟利用基因敲除或过表达小鼠证实GSK3β-Tau通路在七氟醚干扰突触可塑性中的作用，以发现GSK3β-Tau为关键的调控分子通路。本研究将阐明七氟醚通过拮抗NMDA受体和上调GSK3β-Tau信号通路影响海马突触可塑性的机制，为防治吸入麻醉药对发育脑的神经毒性提供新思路，并为早期干预提供新的靶点，具有重要理论意义和应用价值。

中文关键词： 麻醉；突触可塑性；NMDA受体；GSK-3β；Tau磷酸化

英文摘要： Sevoflurane is one of the most common inhalation anesthetics for children. A number of studies have shown that inhalation anesthetics induce neuron apoptosis and synaptic transmission and plasticity deficits in neonatal rodent brain, resulting in learning and memory impairment. However, the mechanisms underlying these inhalation anesthetics-induced effects are still largely unknown. Our previous studies demonstrated that general anesthetics sevoflurane could cause Tau hyperphosphorylation, amyloid beta protein accumulation, microtubule filaments structural abnormalities, and synaptic transmission inhibition in the developing rat brain. In this study we propose that the changes in synaptic plasticity caused by inhalation anesthetics are related to regulation of NMDA receptor subunit composition and function and the subsequent activation of GSK3β-Tau signaling pathway. We will utilize loss of function GSK-3β mutant, Tau knockout, and huaman Tau transgenic mice to investigate neonatal sevoflurane exposure-induced changes in LTP/LTD induction and their underlying mechanisms. The results will clarify a neurotoxic and synaptopathic, NMDA receptor-GSK3β-tau centered, pathway triggered by neonatal sevoflurane anesthesia, and provide a new strategy for preventing the toxicity of inhalation anesthetics in the developing brain. This study will also have important theoretical and clinical significance in reducing cognitive deficits as a result of neonatal anesthesia, and bring significant social and economic benefits to the population.

英文关键词： anesthesia;synaptic plasticity;NMDA receptor;GSK-3β;tau