N型乙酰胆碱受体α7及α4β2亚型对海马CA3区锥体神经元及DG区颗粒细胞的影响及机制

发布时间：2018-04-06 01:12

本文选题：α7尼古丁受体　切入点：α4β2尼古丁受体　出处：《复旦大学》2012年博士论文

【摘要】：N型乙酰胆碱受体,即尼古丁受体,是一种重要的神经递质受体,广泛地存在于中枢神经系统中。胆碱能系统参与包括注意、学习、觉醒和认知等重要的神经系统功能,并且与阿尔茨海默病、帕金森病和精神分裂等神经系统疾病密切相关。N型乙酰胆碱受体是由五个跨膜亚单位构成的阳离子通道。亚单位有多重类型,不同种类的亚单位构成了具有不同性质功能及分布的尼古丁受体亚型,如α2-α10和β2-β4亚单位可形成存在于大脑中的尼古丁受体亚型。在中枢神经系统中,α7和α4β2是分布最广表达量最高的两种尼古丁受体亚型。已有大量证据表明尼古丁及尼古丁受体与学习记忆功能存在密切联系,行为学实验和海马电生理实验都提示α7和a4β2尼古丁受体在认知功能中起到重要作用。海马长时程增强被认为是学习记忆功能的基础,有研究表明α7和α4β2尼古丁受体的激动剂或拮抗剂对海马的长时程增强有调节作用,但其中的机制尚未明确。第一部分课题利用单细胞胞外记录的方法研究了在整体条件下静脉或离子微电泳给予尼古丁或a7尼古丁受体特异性激动剂AR-R17779和PSAB-OFP对于海马CA3锥体神经元兴奋性的影响。实验结果显示静脉或离子微电泳方式给尼古丁或α7尼古丁受体激动剂都可在大部分被记录神经元中引起神经元动作电位发放增加,并且这一作用可被α7尼古丁受体拮抗剂MLA所抑制。离子微电泳给药实验还显示α7受体激动剂所引起的神经元兴奋可被NMDA受体拮抗剂D-AP5或非NMDA受体拮抗剂DNQX所阻断,提示这些尼古丁受体激动剂对CA3锥体神经元的作用机制可能是通过激活谷氨酸能突触前的α7尼古丁受体并导致谷氨酸递质释放的增加。在第二部分课题中,在离体海马脑片上,我们通过puff给药方式研究了α4β2尼古丁受体选择性部分激动剂TC-2559对DG颗粒细胞的影响。结果显示TC-2559抑制了DG区颗粒细胞sEPSC,但不影响mEPSC的频率,而GABAA受体拮抗剂bicuculline可抑制TC-2559的这一作用,这提示了α4β2尼古丁受体的激动可抑制颗粒细胞突触前谷氨酸的释放,这一作用可能是通过多突触的机制介导的并可能有GABA能中间神经元的参与。
[Abstract]:N-type acetylcholine receptor, nicotine receptor, is an important neurotransmitter receptor, which widely exists in the central nervous system.The cholinergic system is involved in important neurological functions, including attention, learning, arousal, and cognition, and is associated with Alzheimer's disease.Type N acetylcholine receptor is a cationic channel composed of five transmembrane subunits closely related to nervous system diseases such as Parkinson's disease and schizophrenia.There are many types of subunits, and different subunits form nicotine receptor subtypes with different function and distribution. For example, 伪 2- 伪 10 and 尾 2- 尾 4 subunits can form nicotine receptor subtypes in the brain.In the central nervous system, 伪 7 and 伪 4 尾 2 are the two most widely expressed nicotine receptor subtypes.A large number of evidences have shown that nicotine and nicotine receptors are closely related to learning and memory function. Both behavioral and hippocampal electrophysiological experiments suggest that 伪 7 and a 4 尾 2 nicotine receptors play an important role in cognitive function.Long-term potentiation of hippocampus is considered to be the basis of learning and memory function. Some studies have shown that agonists or antagonists of 伪 7 and 伪 4 尾 2 nicotine receptors can regulate the long term potentiation of hippocampus, but the mechanism is not clear.In the first part, the effects of intravenous or ionic microelectrophoresis on the excitability of hippocampal CA3 pyramidal neurons were studied by means of single cell extracellular recording. The effects of AR-R17779 and PSAB-OFP on the excitability of hippocampal CA3 pyramidal neurons were studied.The results showed that intravenous or ionic microelectrophoretic administration of nicotine or 伪 7 nicotinic receptor agonists could induce increased action potential release in most of the recorded neurons.And this effect can be inhibited by 伪 7 nicotine receptor antagonist MLA.Ionic microelectrophoretic assay also showed that the activation of neurons induced by 伪 7 receptor agonists could be blocked by NMDA receptor antagonist D-AP5 or non NMDA receptor antagonist DNQX.These results suggest that the mechanism of these nicotine receptor agonists on CA3 pyramidal neurons may be by activating the 伪 7 nicotine receptor presynaptic glutamate and increasing the release of glutamate transmitters.In the second part, we studied the effect of 伪 4 尾 2 nicotinic receptor selective partial agonist (TC-2559) on DG granulosa cells in isolated hippocampal slices by puff administration.The results showed that TC-2559 inhibited the frequency of mEPSC in granular cells of DG region, but bicuculline, the GABAA receptor antagonist, inhibited this effect of TC-2559, suggesting that the activation of 伪 4 尾 2 nicotine receptor could inhibit the release of presynaptic glutamate in granulosa cells.This action may be mediated by polysynaptic mechanisms and may involve GABA-capable interneurons.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R338

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