本文選題：MeCP2　切入點：膽堿能神經(jīng)元　出處：《浙江大學(xué)》2017年博士論文

【摘要】：瑞特綜合癥是一種嚴(yán)重影響人類精神健康的疾病,主要表現(xiàn)為運動能力的異常,社交障礙,認(rèn)知紊亂以及癲癇的高發(fā)性。研究發(fā)現(xiàn)位于X染色體上的MECP2基因是瑞特綜合癥的致病基因,MECP2基因敲除的小鼠可以表現(xiàn)出瑞特綜合癥樣的表型。由于發(fā)病癥狀的廣泛性及特異的神經(jīng)紊亂,瑞特綜合癥至今缺乏有效的治療手段。因此,對瑞特綜合癥發(fā)病機制的研究從而找到相應(yīng)的治療靶點顯得尤為重要。臨床結(jié)果顯示,瑞特綜合癥的嚴(yán)重程度與膽堿能標(biāo)志物的表達(dá)量相一致。膽堿能系統(tǒng)是大腦中的彌散性調(diào)節(jié)系統(tǒng)。主要分布在基底前腦,紋狀體和腦干等腦區(qū),調(diào)控運動,學(xué)習(xí)記憶以及睡眠覺醒等功能。但是,關(guān)于膽堿能系統(tǒng)特別是不同腦區(qū)的膽堿能環(huán)路在瑞特綜合癥致病中的作用卻鮮有報道。因此,本研究結(jié)合電生理,生化以及光遺傳學(xué)等手段,試圖回答三個問題:第一,膽堿能系統(tǒng)是否參與到瑞特綜合癥的致病過程中?第二,瑞特綜合癥是一種多癥狀的神經(jīng)疾病,不同腦區(qū)的膽堿能環(huán)路在各個癥狀中的作用是否相同?我們主要關(guān)注基底前腦和紋狀體這兩個膽堿能相關(guān)腦區(qū)。第三,基底前腦和紋狀體膽堿能神經(jīng)元分別通過怎樣的機制調(diào)節(jié)瑞特綜合癥的癥狀?即能否找到相應(yīng)的分子靶點從而達(dá)到治療的效果?我們發(fā)現(xiàn),在膽堿能系統(tǒng)中敲除MeCP2可以造成部分瑞特綜合癥樣表型,包括焦慮/抑郁相關(guān)行為的改變,社會交往能力的異常,癲癇的易感性以及恐懼記憶的缺失。為了研究不同腦區(qū)的膽堿能神經(jīng)元對瑞特綜合癥的作用,我們分別在基底前腦以及紋狀體膽堿能神經(jīng)元上恢復(fù)MeCP2的表達(dá),結(jié)果發(fā)現(xiàn),在基底前腦膽堿能神經(jīng)元上重新表達(dá)MeCP2可以特異性逆轉(zhuǎn)Chat-Mecp2~(-/y)小鼠焦慮/抑郁相關(guān)行為,社會交往能力的改變。在紋狀體膽堿能神經(jīng)元上重新表達(dá)MeCP2可以特異性改善Chat-Mecp2~(-/y)小鼠的恐懼編碼能力。接下來,我們分成兩個部分分別探討不同腦區(qū)的膽堿能神經(jīng)元在瑞特綜合癥相關(guān)癥狀發(fā)生中的分子機制。第一部分:基底前腦:在膽堿能系統(tǒng)中敲除MeCP2影響了基底前腦到海馬的膽堿能神經(jīng)環(huán)路,使得海馬PV神經(jīng)元上α7乙酰膽堿受體的表達(dá)降低。海馬定點給藥PNU282987或尼古丁都可以逆轉(zhuǎn)Chat-Mecp2~(-/y)小鼠的行為學(xué)表型。第二部分:紋狀體:在膽堿能系統(tǒng)中敲除MeCP2使得紋狀體膽堿能神經(jīng)元上α2GABAA受體的表達(dá)上調(diào),增加的抑制性輸入造成紋狀體神經(jīng)元興奮性降低。用RNA干擾的方法敲減α2 GABAA受體或者直接興奮膽堿能神經(jīng)元都可以逆轉(zhuǎn)Chat-Mecp2~(-/y)小鼠的恐懼記憶行為。紋狀體膽堿能神經(jīng)元是一種中間神經(jīng)元,可以調(diào)控整個紋狀體環(huán)路,用光遺傳的方法興奮紋狀體神經(jīng)元也可以改善恐懼記憶的編碼。
[Abstract]:Ritter syndrome is a disease that severely affects human mental health. It is characterized by abnormal motor ability, social disorder, cognitive disorder and high incidence of epilepsy.It was found that the MECP2 gene located on the X chromosome was the pathogenic gene of Ruit syndrome, and that the mice knockout the MECP2 gene could exhibit the Ruit syndrome like phenotype.Due to the prevalence of symptoms and specific neurological disorders, Rhett syndrome has not been effective treatment.Therefore, it is very important to study the pathogenesis of Rhett syndrome and find the corresponding therapeutic target.The clinical results showed that the severity of Rhett syndrome was consistent with the expression of cholinergic markers.The cholinergic system is a diffuse regulatory system in the brain.It is mainly distributed in the basal forebrain, striatum and brain stem, regulating motor, learning and memory, and sleep arousal.However, the role of cholinergic system, especially the cholinergic loop in different brain regions, in the pathogenesis of Rhett syndrome is rarely reported.Therefore, this study combines electrophysiology, biochemistry and photogenetics to answer three questions: first, is the cholinergic system involved in the pathogenesis of Rhett syndrome?Second, Ritter syndrome is a multi-symptomatic neurological disease. Does the cholinergic loop in different brain regions play the same role in each symptom?We focus on the basal forebrain and striatum, the two cholinergic related brain regions.Third, how do basal forebrain and striatal cholinergic neurons regulate the symptoms of Rhett syndrome?That is, can we find the corresponding molecular target to achieve the therapeutic effect?We found that knockout of MeCP2 in the cholinergic system resulted in a portion of the Rhett syndrome phenotype, including changes in anxiety / depression-related behavior, abnormal social interaction, susceptibility to epilepsy, and loss of fear and memory.In order to study the effect of cholinergic neurons in different brain regions on the expression of MeCP2 in basal forebrain and striatal cholinergic neurons, we found that,The reexpression of MeCP2 in basal forebrain cholinergic neurons can specifically reverse the anxiety / depression-related behavior and the change of social communication ability in Chat-Mecp2- / -rymice.Reexpression of MeCP2 on striatal cholinergic neurons can specifically improve the fear coding ability of Chat-Mecp2- / -rymice.Next, we divided into two parts to explore the molecular mechanism of cholinergic neurons in different brain regions in the pathogenesis of Ruit syndrome related symptoms.Part I: basal forebrain: knockout of MeCP2 in cholinergic system affects cholinergic nerve loop from basal forebrain to hippocampus and reduces the expression of 偽 7 acetylcholine receptor in hippocampal PV neurons.Hippocampal targeted administration of either PNU282987 or nicotine could reverse the behavioral phenotype of Chat-Mecp2-/ -rymice.The second part: striatum: knockout of MeCP2 in the cholinergic system up-regulates the expression of 偽 2GABAA receptor in striatal cholinergic neurons, resulting in decreased excitability of striatal neurons due to increased inhibitory input.Knockout of 偽 2 GABAA receptor or direct stimulation of cholinergic neurons by RNA interference can reverse the fear memory behavior in Chat-Mecp2- / -rymice.Striatal cholinergic neurons are intermediate neurons which can regulate the entire striatal loop. The stimulation of striatal neurons by photogenetic method can also improve the coding of fear memory.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R741

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