NR1亚基C末端剪接异构体对NMDA受体功能的调节

发布时间：2018-04-14 00:28

本文选题：长时程增强 + NMDA受体　；参考：《上海交通大学》2009年硕士论文

【摘要】： NMDA受体广泛表达于中枢神经系统,介导突触可塑性的形成,调控神经元的基因表达,参与发育过程中神经网络的形成。它是大脑学习与记忆功能的关键因子,同时过度激活也可导致神经元坏死和细胞凋亡等神经损害。NR1是功能性NMDA受体的必需亚基,其C末端由于2个外显子的可变剪接而具有分子生物学多样性,在很大程度上决定了NMDA受体复杂多样的功能。多年来很多研究都提示NR1亚基C末端对受体通道功能的调控,靶向运输及基因表达等方面起着重要的作用,但其具体的功能及其机制还未完全阐明。而且这些研究大多是针对在异源系统或体外培养的神经细胞中表达的重组受体进行的,而重组受体一般会失去生理状态下细胞内环境中很多信号分子或结构蛋白的作用,而且这种方法使得我们无法对其在突触可塑性中的作用进行研究。因此,有必要构建一种C末端特定区段缺失的转基因动物模型,从而在能够较好模拟在体环境的条件中进行C末端剪接异构体的功能研究。本研究中,我们利用合作研究单位构建的NR1亚基C末端C1、C2两个外显子被敲除的NR1dC1,C2小鼠,在海马切片中进行了NMDA受体通道性质的系统的检测。我们的研究结果显示NR1dC1,C2小鼠其NMDA受体电流在强刺激、高频刺激、或者双刺激的条件下反应性减弱,LTP的形成受到抑制。由此我们推测在海马CA1神经元内NR1亚基的C1和/或C2参与CDI的调控,而C1和C2的缺失导致了CDI程度的增强,使得高频刺激以及双刺激下NMDA受体介导的Ca2+内流受到抑制,使得LTP的形成受到影响。我们的以上研究为进一步深入揭示NR1亚基C1和C2外显子的功能提供了新的线索。
[Abstract]:NMDA receptors are widely expressed in the central nervous system, mediate the formation of synaptic plasticity, regulate the gene expression of neurons, and participate in the formation of neural networks during development.It is a key factor in the learning and memory function of the brain, and excessive activation can also lead to neuronal necrosis and apoptosis. NR1 is an essential subunit of functional NMDA receptor.Its C-terminal has molecular biological diversity due to the variable splicing of two exons, which to a great extent determines the complex and diverse functions of NMDA receptors.Many studies have suggested that the C-terminal of NR1 subunit plays an important role in regulation of receptor channel function, targeted transport and gene expression, but its specific function and mechanism have not been fully elucidated.And most of these studies are directed at recombinant receptors expressed in xenogeneic systems or in cultured nerve cells, which typically lose the role of many signaling molecules or structural proteins in the cellular environment under physiological conditions.And this method makes it impossible to study its role in synaptic plasticity.Therefore, it is necessary to construct a transgenic animal model with missing specific segments of C-terminal, so as to study the function of C-terminal splicing isomers under the condition of better simulation in vivo.In this study, we used co-constructed NR1dC1C2-2 exons of NR1 subunit to detect the properties of NMDA receptor channels in hippocampal slices of NR1dC1C1-C 2 mice.Our results showed that the NMDA receptor current in NR1dC1C 2 mice was inhibited under the condition of strong stimulation, high frequency stimulation, or double stimulation.Therefore, we speculate that C1 and / or C2 of NR1 subunit in hippocampal CA1 neurons are involved in the regulation of CDI, and the deletion of C1 and C2 leads to the enhancement of CDI degree, which inhibits Ca2 influx mediated by NMDA receptor under high frequency stimulation and double stimulation.The formation of LTP is affected.Our study provides a new clue to further reveal the function of exons C1 and C2 of NR1 subunits.
【学位授予单位】：上海交通大学
【学位级别】：硕士
【学位授予年份】：2009
【分类号】：R341

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