本文選題：α7尼古丁受體　切入點：α4β2尼古丁受體　出處：《復旦大學》2012年博士論文

【摘要】：N型乙酰膽堿受體,即尼古丁受體,是一種重要的神經(jīng)遞質(zhì)受體,廣泛地存在于中樞神經(jīng)系統(tǒng)中。膽堿能系統(tǒng)參與包括注意、學習、覺醒和認知等重要的神經(jīng)系統(tǒng)功能,并且與阿爾茨海默病、帕金森病和精神分裂等神經(jīng)系統(tǒng)疾病密切相關(guān)。N型乙酰膽堿受體是由五個跨膜亞單位構(gòu)成的陽離子通道。亞單位有多重類型,不同種類的亞單位構(gòu)成了具有不同性質(zhì)功能及分布的尼古丁受體亞型,如α2-α10和β2-β4亞單位可形成存在于大腦中的尼古丁受體亞型。在中樞神經(jīng)系統(tǒng)中,α7和α4β2是分布最廣表達量最高的兩種尼古丁受體亞型。已有大量證據(jù)表明尼古丁及尼古丁受體與學習記憶功能存在密切聯(lián)系,行為學實驗和海馬電生理實驗都提示α7和a4β2尼古丁受體在認知功能中起到重要作用。海馬長時程增強被認為是學習記憶功能的基礎(chǔ),有研究表明α7和α4β2尼古丁受體的激動劑或拮抗劑對海馬的長時程增強有調(diào)節(jié)作用,但其中的機制尚未明確。第一部分課題利用單細胞胞外記錄的方法研究了在整體條件下靜脈或離子微電泳給予尼古丁或a7尼古丁受體特異性激動劑AR-R17779和PSAB-OFP對于海馬CA3錐體神經(jīng)元興奮性的影響。實驗結(jié)果顯示靜脈或離子微電泳方式給尼古丁或α7尼古丁受體激動劑都可在大部分被記錄神經(jīng)元中引起神經(jīng)元動作電位發(fā)放增加,并且這一作用可被α7尼古丁受體拮抗劑MLA所抑制。離子微電泳給藥實驗還顯示α7受體激動劑所引起的神經(jīng)元興奮可被NMDA受體拮抗劑D-AP5或非NMDA受體拮抗劑DNQX所阻斷,提示這些尼古丁受體激動劑對CA3錐體神經(jīng)元的作用機制可能是通過激活谷氨酸能突觸前的α7尼古丁受體并導致谷氨酸遞質(zhì)釋放的增加。在第二部分課題中,在離體海馬腦片上,我們通過puff給藥方式研究了α4β2尼古丁受體選擇性部分激動劑TC-2559對DG顆粒細胞的影響。結(jié)果顯示TC-2559抑制了DG區(qū)顆粒細胞sEPSC,但不影響mEPSC的頻率,而GABAA受體拮抗劑bicuculline可抑制TC-2559的這一作用,這提示了α4β2尼古丁受體的激動可抑制顆粒細胞突觸前谷氨酸的釋放,這一作用可能是通過多突觸的機制介導的并可能有GABA能中間神經(jīng)元的參與。
[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, 偽 2- 偽 10 and 尾 2- 尾 4 subunits can form nicotine receptor subtypes in the brain.In the central nervous system, 偽 7 and 偽 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 偽 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 偽 7 and 偽 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 偽 7 nicotinic receptor agonists could induce increased action potential release in most of the recorded neurons.And this effect can be inhibited by 偽 7 nicotine receptor antagonist MLA.Ionic microelectrophoretic assay also showed that the activation of neurons induced by 偽 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 偽 7 nicotine receptor presynaptic glutamate and increasing the release of glutamate transmitters.In the second part, we studied the effect of 偽 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 偽 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.
【學位授予單位】：復旦大學
【學位級別】：博士
【學位授予年份】：2012
【分類號】：R338

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