基于NMDARs对突触可塑性的调控在微波辐射致学习记忆障碍长期效应中作用的基础研究

It has been reported that the brain is the most sensitive target of microwave radiation. Microwave radiation can cause the impairment of learning and memory function and the damage of synaptic plasticity, but the mechanism is unknown. Synaptic plasticity is the neural basis of learning and memory. NMDARs have played an indispensable role for the regulation of synaptic plasticity and learning and memory function. Previous studies mainly focused on the immediate or short term effects of microwave radiation. Few studies to date have been conducted on the long-term effects of microwave exposure on learning and memory based on role of NMDARs regulation on synaptic plasticity. Therefore, the present study was firstly intended to use an appropriate animal paradigm and investigate the relationship between the microwave induced learning and memory impairment and synaptic plasticity injuries and changes of LTP and NMDARs. Furthermore, we intended to establish the cell model of synaptic plasticity damage caused by microwave radiation and to explore the NMDARs channel potential changes of primary hippocampal neurons by the patch-clamp technique. Besides, we planned to study the relationship between changes of NR1, NR2A and NR2B and injuries of synaptic plasticity by the gene over expression or RNA interference technology, looking forward to establish the theoretical basis for finding the sensitive indicators and the targets for prevention and treatment of microwave induced brain damage.

研究表明，脑是微波辐射最为敏感的靶部位，微波辐射可引起学习记忆障碍及突触可塑性损伤，但目前机制不明。学习和记忆的神经基础是突触可塑性，NMDARs对于突触可塑性的调控及学习和记忆功能的发挥起到不可或缺的作用。既往的研究多集中于微波辐射后即刻或近期效应，基于NMDARs对突触可塑性的调控在微波辐射致学习记忆障碍长期效应中作用研究尚属空白。为此，本研究拟首先建立微波辐射致学习记忆障碍和突触可塑性损伤的长期动物模型，探讨微波辐射致学习记忆障碍、突触可塑性损伤与LTP和NMDARs改变的关系；进而复制微波辐射致突触可塑性损伤的细胞模型，采用膜片钳技术探讨微波辐射致原代海马神经元NMDARs通道电位变化；最后运用基因过表达或RNA干扰等技术研究微波辐射后NMDARs重要亚基NR1、NR2A和NR2B的改变及其与突触可塑性损伤之间的关系，为寻找微波辐射致脑损伤的敏感指标和防治靶点奠定理论基础。

脑是微波辐射最为敏感部位，学习和记忆的神经基础是突触可塑性，N-甲基-D-天门冬氨受体（NMDARs）对于突触可塑性的调节及LTP的诱导和维持起到不可或缺作用。既往研究集中于微波辐射后即刻或近期效应与机制，基于NMDARs对突触可塑性的调控在微波辐射致学习记忆障碍长期效应中作用研究尚属空白。为此，本研究建立了微波辐射致学习记忆障碍和突触可塑性损伤的长期动物模型，探讨了微波辐射致突触可塑性损伤与LTP和NMDARs的关系；复制了微波辐射致突触可塑性损伤的细胞模型，采用膜片钳技术探讨了微波辐射致神经元NMDARs通道电位变化；最后研究微波辐射后NMDARs重要亚基NR1、NR2A和NR2B的改变及其与突触可塑性损伤间的关系。.本项目主要研究发现：（1）5mW/cm2微波辐射未见显著损伤，10和50mW/cm2微波辐射可致大鼠远后期学习和记忆功能下降及突触可塑性损伤，表现为空间学习和记忆功能下降、氨基酸递质含量下降、部分海马神经元核固缩及超微结构损伤及LTP诱导障碍，且与辐射剂量呈正相关。（2）NMDARs参与微波辐射致突触可塑性损伤的病理生理过程；NR2B保护作用减弱可能是远后期大鼠学习记忆功能下降重要原因。（3）50mW/cm2微波辐射可致大鼠原代海马神经元突触可塑性损伤，表现为神经元突起长度缩短、数量减少、断裂发生；NMDARs受体功能降低，表现为NR1、NR2A和NR2B的mRNA降低和NR2A、NR2B和p-NR2B蛋白表达降低及通道电流减少。（4）NMDARs激动剂可保护微波辐射所致的神经元突触可塑性损伤，表现为突起长度、数量，NMDARs亚基的mRNA和蛋白表达及通道电流等呈恢复性改变。. 本研究发表SCI论文4篇，综述1篇，中文核心期刊论文1篇；获中国体视学会科技进步一等奖1项；参加国际学术会议1次，国内学术会议3次，大会报告1篇，获优秀论文1篇；申请国家发明专利5项，培养博士生2名、硕士生1名。本研究将为阐明微波辐射致学习记忆障碍长期效应中突触可塑性改变的分子机制、寻找敏感生物标志物和防治靶点奠定基础，具有重要的理论意义和实际应用价值。