孟怡辰(綜述),高霄飛(審校)
(1.第二軍醫(yī)大學(xué)臨床醫(yī)學(xué)八年制2009級(jí),上海 200433; 2.第二軍醫(yī)大學(xué)神經(jīng)生物學(xué)教研室,上海 200433)
突觸的可塑性是指在外界環(huán)境改變的條件下,突觸之間連接、傳遞效率發(fā)生變化的能力。突觸效率的改變使神經(jīng)元之間聯(lián)系增強(qiáng),能夠促進(jìn)記憶的形成。突觸可塑性在記憶形成過(guò)程中對(duì)信息的儲(chǔ)存起到了重要作用。有報(bào)道稱突觸可塑性就是學(xué)習(xí)記憶的機(jī)制[1]。突觸可塑性從時(shí)間上可以分為短時(shí)程和長(zhǎng)時(shí)程突觸可塑性,其中長(zhǎng)時(shí)程突觸可塑性的重要表現(xiàn)形式是長(zhǎng)時(shí)程增強(qiáng)(long-term potentiation,LTP)。LTP是指突觸前末梢受到強(qiáng)直刺激后,突觸后神經(jīng)元出現(xiàn)的一種突觸后電位持續(xù)性增強(qiáng)現(xiàn)象。LTP被認(rèn)為是學(xué)習(xí)記憶的神經(jīng)基礎(chǔ),是研究學(xué)習(xí)和記憶的理想模型[2]。Bliss等[3]對(duì)家兔穿通通路進(jìn)行高頻刺激,發(fā)現(xiàn)齒狀回突觸傳遞效率明顯持續(xù)增高的現(xiàn)象,首次提出了LTP現(xiàn)象,此后,LTP現(xiàn)象備受神經(jīng)科學(xué)界關(guān)注。突觸聯(lián)系所在部位不同,LTP產(chǎn)生機(jī)制也不同。本文對(duì)海馬部位突觸后LTP的可能分子機(jī)制進(jìn)行綜述。
LTP產(chǎn)生的關(guān)鍵步驟是突觸后細(xì)胞鈣離子的內(nèi)流。突觸后細(xì)胞有豐富鈣離子時(shí)有利于產(chǎn)生LTP,研究發(fā)現(xiàn)鉀離子通道Kv7被阻斷能夠增強(qiáng)鈣離子內(nèi)流,進(jìn)而促進(jìn)LTP的產(chǎn)生[4-5]。在絕大多數(shù)可以產(chǎn)生LTP的突觸中,N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid,NMDA)受體的激活介導(dǎo)突觸后細(xì)胞內(nèi)鈣離子的積累。突觸后膜除極,谷氨酸結(jié)合并激活NMDA受體,使鈣離子通道打開(kāi)[6]。隨后,進(jìn)入的鈣離子激活一系列下游信號(hào)通路的酶,包括鈣調(diào)蛋白依賴性蛋白激酶Ⅱ和蛋白激酶C。鈣調(diào)蛋白依賴性蛋白激酶Ⅱ的激活可誘導(dǎo)海馬CA1區(qū)產(chǎn)生LTP;鈣調(diào)蛋白依賴性蛋白激酶Ⅱ誘導(dǎo)LTP的途徑為胞內(nèi)鈣離子與鈣調(diào)蛋白結(jié)合增加,形成的復(fù)合物除去自身抑制序列的鄰近序列,與鈣調(diào)蛋白依賴性蛋白激酶Ⅱ結(jié)合,使鈣調(diào)蛋白依賴性蛋白激酶Ⅱ發(fā)生自身磷酸化,鈣調(diào)蛋白依賴性蛋白激酶Ⅱ可以移位至突觸后密集區(qū)(postsynaptic density,PSD),與α-輔肌動(dòng)蛋白、PSD95、突觸黏附分子等PSD上的蛋白結(jié)合;結(jié)合后的復(fù)合物促進(jìn)α-氨基羥甲基惡唑丙酸(alpha amino hydroxy methyl oxazole propionic acid,AMPA)受體在突觸后膜上的錨定,增強(qiáng)突觸后膜受體的敏感性進(jìn)而影響LTP的產(chǎn)生,而且鈣調(diào)蛋白依賴性蛋白激酶Ⅱ的激活能夠產(chǎn)生逆行信使影響神經(jīng)遞質(zhì)的釋放,間接影響LTP的誘導(dǎo)產(chǎn)生[7-8]。
鈣離子通過(guò)谷氨酸受體進(jìn)入胞內(nèi)。NMDA受體是一種分布于突觸后膜的化學(xué)、電壓雙門控的特殊離子通道,因其既需要電壓信號(hào)又需要遞質(zhì)才能激活的特性被稱為“同時(shí)性檢測(cè)器”,其對(duì)鈣離子有較強(qiáng)的通透性[6]。NMDA受體活性及其亞基類型數(shù)量的改變均可以誘導(dǎo)LTP[7]。證明NMDA受體誘導(dǎo)LTP產(chǎn)生的有力證據(jù)是應(yīng)用NMDA受體拮抗劑美金胺可以抑制LTP的產(chǎn)生[9]。
NMDA受體亞基類型的數(shù)量變化能夠影響LTP的產(chǎn)生。NMDA受體主要由NR1和NR2兩種亞基按照一定比例構(gòu)成,在腦的不同部位兩種亞基表達(dá)數(shù)量不同[10-11]。研究證實(shí),敲除NR2A或者NR2B亞基均可導(dǎo)致LTP產(chǎn)生不完全[11-12];隨著NMDA受體亞基NR2B的表達(dá)增加,海馬CA1區(qū)的LTP也會(huì)隨之增強(qiáng)[13]。馬達(dá)分子驅(qū)動(dòng)蛋白族成員17(kinesin family member,KIF17)在哺乳動(dòng)物神經(jīng)元中大量表達(dá),被認(rèn)為是NR2B囊泡的轉(zhuǎn)運(yùn)體[14]。近期研究發(fā)現(xiàn),腺苷環(huán)磷酸反應(yīng)原件結(jié)合蛋白介導(dǎo)KIF17和NR2B的高水平表達(dá),使得KIF17轉(zhuǎn)運(yùn)NR2B能力增強(qiáng),加快了NMDA受體的合成,產(chǎn)生更加穩(wěn)定的LTP[15]。也有研究發(fā)現(xiàn),腦額葉前皮質(zhì)NR2B亞基的過(guò)度表達(dá)能夠促進(jìn)額葉前皮質(zhì)LTP的產(chǎn)生[16-17]。需鈣蛋白酶被鈣離子激活后可以降解NMDA受體,使之在PSD上的數(shù)量減少。細(xì)胞周期依賴蛋白激酶5可以調(diào)控需鈣蛋白酶對(duì)NR2B亞基的降解作用,細(xì)胞周期依賴蛋白激酶5基因敲除的成年大鼠NR2B降解減少,NMDA介導(dǎo)的電流增強(qiáng),LTP隨之增強(qiáng)。孤啡肽受體敲除的小鼠LTP顯著增強(qiáng),表明孤啡肽受體也可以影響突觸可塑性,其具體機(jī)制仍不清楚,但敲除孤啡肽受體可以增強(qiáng)NMDA受體功能并更快地激活下游α鈣調(diào)蛋白依賴性蛋白激酶Ⅱ[18]。
研究發(fā)現(xiàn),需鈣蛋白酶可以通過(guò)截短一系列細(xì)胞骨架蛋白對(duì)細(xì)胞形狀進(jìn)行調(diào)控[19]。神經(jīng)元中內(nèi)流的鈣離子激活需鈣蛋白酶,解離肌動(dòng)蛋白細(xì)胞骨架并使部分黏附分子受體失活。腦源性神經(jīng)營(yíng)養(yǎng)因子(brain-derived neurotrophic factor,BDNF)對(duì)LTP的產(chǎn)生具有重要作用,而其發(fā)揮作用的可能機(jī)制就是通過(guò)細(xì)胞外調(diào)節(jié)蛋白激酶介導(dǎo)的磷酸化增強(qiáng)需鈣蛋白酶的活性[20-21]。
LTP主要通過(guò)突觸后膜細(xì)胞骨架的改變而實(shí)現(xiàn)。PSD是突觸后膜細(xì)胞骨架纖維特化區(qū)域,調(diào)節(jié)細(xì)胞黏附性和受體聚集、功能[22]。PSD上有3種跨膜受體分別負(fù)責(zé)接受谷氨酸神經(jīng)遞質(zhì)、黏附、調(diào)節(jié),靜息狀態(tài)下的突觸后膜是一個(gè)處于相對(duì)穩(wěn)定狀態(tài)的細(xì)胞骨架結(jié)構(gòu),由膜收縮蛋白及其他蛋白交聯(lián)形成的肌動(dòng)蛋白纖維構(gòu)成。PSD上的調(diào)節(jié)受體被稱為突觸調(diào)節(jié)子,包括腺苷A1受體、雌激素β受體以及BDNF的酪氨酸激酶受體B[23-27]。BDNF和雌激素能夠促進(jìn)突觸后膜細(xì)胞骨架的變構(gòu),而腺苷具有相反的作用,這三者作用于兩條Rho鳥(niǎo)苷三磷酸酶相關(guān)的肌動(dòng)蛋白信號(hào)途徑,共同調(diào)節(jié)LTP的維持時(shí)間和強(qiáng)度[23]。第一條途徑由RhoA及效應(yīng)物等參與。正絲切蛋白是一類高活性能切斷肌動(dòng)蛋白的蛋白質(zhì),它的磷酸化能夠影響細(xì)胞骨架的聚合[28];第二條途徑由Rac、細(xì)胞分裂周期蛋白42及p21激活性激酶等參與。p21激活性激酶已被證實(shí)在多種細(xì)胞內(nèi)參與細(xì)胞骨架的重組[29]。雌激素激活RhoA,促進(jìn)肌動(dòng)蛋白聚合和LTP形成,而雌激素抑制劑可以明顯影響LTP的產(chǎn)生[30]。卵巢切除的中年小鼠LTP產(chǎn)生障礙,可對(duì)其注射雌激素進(jìn)行治療[28]。腺苷阻斷RhoA的作用,使Rho鳥(niǎo)苷三磷酸酶利用率降低,從而抑制LTP。雌激素和腺苷都作用于第一條途徑;BDNF同時(shí)作用于兩條途徑。BDNF是研究最廣的LTP調(diào)控因子,它對(duì)肌動(dòng)蛋白細(xì)胞骨架的影響非常強(qiáng)烈。研究發(fā)現(xiàn),清除BDNF能夠阻斷肌動(dòng)蛋白的聚合作用,同時(shí)阻斷LTP;卵巢切除的大鼠由于缺乏雌激素可觀察到細(xì)胞骨架重組和LTP的異常,而B(niǎo)DNF的上調(diào)則可以使這種異?;謴?fù)[25,27,31]。
AMPA受體作為突觸后膜上的一種重要受體,可以被鈣離子/鈣調(diào)蛋白依賴性蛋白激酶Ⅱ復(fù)合體磷酸化而具有更強(qiáng)的通透性,但是AMPA受體功能的改變主要是由于突觸后膜上數(shù)量的改變,PSD結(jié)構(gòu)的改變?yōu)锳MPA受體提供了更多的錨定位點(diǎn)。AMPA受體調(diào)控LTP主要通過(guò)改變膜上和胞內(nèi)AMPA受體數(shù)量的比例[32-33]。有研究發(fā)現(xiàn),雷神之酶(thorase)通過(guò)分解羥基-5-甲基-4-異惡唑受體-谷氨酸受體相互作用蛋白1復(fù)合物,介導(dǎo)AMPA受體的內(nèi)化作用,雷神之酶過(guò)度表達(dá)使突觸后膜上AMPA受體數(shù)量減少,進(jìn)而對(duì)LTP進(jìn)行調(diào)控[34]。被認(rèn)為與記憶有關(guān)的基因KIBRA,也能通過(guò)調(diào)控AMPA受體的循環(huán)使膜上AMPA受體數(shù)量發(fā)生變化,影響LTP的維持[35]。
以上總結(jié)了LTP在誘導(dǎo)和增強(qiáng)兩個(gè)階段的可能分子機(jī)制。LTP的誘導(dǎo)表達(dá)及維持是受到多種受體、物質(zhì),多條信號(hào)途徑協(xié)同影響的一個(gè)連續(xù)復(fù)雜過(guò)程。LTP產(chǎn)生和維持的機(jī)制正在不斷被發(fā)現(xiàn),隨著深入地研究,將會(huì)有更多的影響因素被發(fā)現(xiàn)。動(dòng)態(tài)觀察所有因素在環(huán)路中的調(diào)控作用是一個(gè)難題,還需要更清楚地掌握突觸的納米結(jié)構(gòu),采取更先進(jìn)的檢測(cè)方法,能夠在活體動(dòng)物體內(nèi)研究可塑性通路。這樣的研究對(duì)于LTP的具體機(jī)制以及腦功能的認(rèn)識(shí)、腦潛能的開(kāi)發(fā)等都會(huì)產(chǎn)生深刻影響。
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