劉志國， 張宏宇， 王華林， 王麗梅， 劉烈炬

武漢輕工大學(xué)生物與制藥工程學(xué)院，武漢 430023

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ω-3多不飽和脂肪酸對(duì)大腦突觸結(jié)構(gòu)和傳遞功能影響的研究進(jìn)展*

劉志國， 張宏宇， 王華林， 王麗梅， 劉烈炬△

武漢輕工大學(xué)生物與制藥工程學(xué)院，武漢 430023

-3多不飽和脂肪酸； 大腦功能； 突觸傳遞； 神經(jīng)細(xì)胞； 受體

當(dāng)突觸前釋放的谷氨酸遞質(zhì)與突觸后膜谷氨酸受體結(jié)合后，可觸發(fā)一系列連鎖反應(yīng)，導(dǎo)致突觸功能的持續(xù)增強(qiáng)或減弱，形成長時(shí)程增強(qiáng)(long term potentiation，LTP)或長時(shí)程抑制(long term depression，LTD)。突觸后谷氨酸受體可分為促離子型受體和促代謝型受體2種類型。促離子型受體可再分為海人藻酸(kainic acid，KA)受體、AMPA(2-amino-3-propionic acid)受體和NMDA(N-methyl-d-aspartate)受體(包括NR1、NR2A、NR2B等亞型)。促代謝型受體包括mGluR1～8等亞型。LTP的形成主要依靠蛋白激酶，如CaMKⅡ(calcium-calmodulin-dependent protein kinase Ⅱ)，使目標(biāo)蛋白，如CREB(cyclic adenosine monophosphate response element binding protein)等磷酸化，導(dǎo)致突觸后膜AMPA受體增加，突觸傳遞功能增強(qiáng)。不同于LTP，LTD的產(chǎn)生主要依靠鈣依賴性磷酯酶對(duì)目標(biāo)蛋白的去磷酸化作用。突觸后磷酸酯酶可導(dǎo)致突觸AMPA受體內(nèi)吞，從而減少對(duì)谷氨酸遞質(zhì)的敏感性。

遞質(zhì)在突觸前神經(jīng)元末梢的釋放包括神經(jīng)遞質(zhì)的合成、囊泡的形成、動(dòng)員(mobilization)、擺渡(trafficking)、錨泊(targeting)、融合(fusion)和出胞(exocytosis)等過程。膜脂質(zhì)是大腦質(zhì)膜主要的組件，對(duì)出胞、擺渡、內(nèi)吞起著重要的作用[11]。-3 PUFA(特別是DHA)作為膜的重要成分，可通過影響大腦質(zhì)膜的特性或是作為游離脂肪酸對(duì)突觸前谷氨酸遞質(zhì)釋放進(jìn)行干預(yù)[12]。-3 PUFA可以促進(jìn)囊泡的更新和出胞過程。適量的-3 PUFA可以增加神經(jīng)遞質(zhì)的釋放并提高突觸的傳遞效率[13]。在富含DHA的培養(yǎng)液中，胚胎海馬神經(jīng)元自發(fā)突觸電流振幅和頻率均高于對(duì)照，而這種突觸活動(dòng)增加主要發(fā)現(xiàn)于谷氨酸類神經(jīng)元[4]。

已釋放的遞質(zhì)通常經(jīng)突觸前末梢重?cái)z取，或被酶代謝消除。星形膠質(zhì)細(xì)胞在谷氨酸和GABA神經(jīng)元突觸間遞質(zhì)的清除中扮演重要的角色[1]，同時(shí)是-3 PUFA調(diào)節(jié)突觸傳遞功能的重要靶點(diǎn)。星形膠質(zhì)細(xì)胞可根據(jù)信號(hào)的強(qiáng)度，通過谷氨酸的攝取和運(yùn)輸以及對(duì)突觸小體體積的調(diào)節(jié)，將谷氨酸的濃度維持在一定的安全范圍內(nèi)[18-19]。過度的刺激(如應(yīng)激反應(yīng))以及星形膠質(zhì)細(xì)胞調(diào)制功能的下降都會(huì)破壞谷氨酸能神經(jīng)元突觸內(nèi)環(huán)境的穩(wěn)定，導(dǎo)致谷氨酸的濃度過高，引起神經(jīng)細(xì)胞興奮中毒(excitotoxicity)以致死亡。上述過程與衰老和多種疾病引起的腦損傷密切相關(guān)[19]。

PUFA除了通過影響突觸前膜遞質(zhì)的釋放和突觸后膜受體的活動(dòng)而調(diào)節(jié)突觸傳遞功能外，還可以通過從神經(jīng)和神經(jīng)膠質(zhì)細(xì)胞質(zhì)膜分離出來的游離脂肪酸(特別是DHA和AA)，作為體內(nèi)重要的信號(hào)分子，參與體內(nèi)信號(hào)轉(zhuǎn)導(dǎo)，涉及肌醇磷脂信使系統(tǒng)[28]、類花生酸信號(hào)轉(zhuǎn)導(dǎo)系統(tǒng)[29]以及磷脂酰肌醇-3激酶(PI3K)-AKT通路等[30]。磷脂酶是決定局部游離脂肪酸可用度的關(guān)鍵酶。磷脂酶包括3種重要的亞型，即磷脂酶A2(Phospholipase A2，PLA2)、磷脂酶C(phospholipase C，PLC)和磷脂酶D(phospholipase D，PLD)。3種磷脂酶分別作用于磷脂中的不同基團(tuán)，產(chǎn)生不同的酶解產(chǎn)物。在哺乳動(dòng)物細(xì)胞中包含多種PLA2的同工酶，例如分泌型磷脂酶A2(sPLA2)、胞漿型磷脂酶A2(cPLA2，Ca2+依賴型磷脂酶)和Ca2+非依賴型磷脂酶A2(iPLA2)等。PLA2可直接催化磷脂sn-2脂酰鍵的水解，產(chǎn)生AA、DHA和溶血磷脂。PLC和PLD則不能直接產(chǎn)生AA，但可以通過AA的前體，二酰甘油(DAG)或磷脂酸(PA)釋放AA。釋放出的AA或成為逆行信使(retrograde messenger)[31]，或通過各種代謝酶類(如環(huán)氧酶、脂氧合酶和加雙氧酶等)生成多種類花生酸物質(zhì)，如前列腺素、白細(xì)胞三烯和凝血蒽烷等[32]。類花生酸在機(jī)體炎性反應(yīng)中起著重要的作用。不同的是，類花生酸主要產(chǎn)生的是促炎因子，而DHA主要產(chǎn)生抗炎因子[32]。

如前所述，谷氨酸是腦內(nèi)主要的興奮性神經(jīng)元，而γ-氨基丁酸(GABA)則是主要的抑制性神經(jīng)元。GABA在大腦皮層淺層和小腦浦肯野細(xì)胞層含量最高，同時(shí)存在于新紋狀體內(nèi)的中間神經(jīng)元。GABA受體可分為GABAa、GABAb和GABAc等3種類型。GABAa和GABAc屬于離子通道型受體，與Cl-通道偶聯(lián)。GABAb屬于代謝型受體。GABAa和GABAb廣泛分布于中樞神經(jīng)系統(tǒng)，參與了神經(jīng)系統(tǒng)的各種功能。雖然GABA能神經(jīng)元分布的區(qū)域與大腦的認(rèn)知功能密切相關(guān)，但GABA能神經(jīng)系統(tǒng)是否參與了-3 PUFA增強(qiáng)學(xué)習(xí)記憶的功能，只是在近年來才開始有所關(guān)注。雖然與谷氨酸相比，我們對(duì)GABA的作用知道得很少，然而卻是探討-3 PUFA作用機(jī)制的一個(gè)新的重要領(lǐng)域。實(shí)驗(yàn)發(fā)現(xiàn)高飽和脂肪酸飲食可以導(dǎo)致海馬和下丘腦GABAa、5-HT1及CB1與受體的結(jié)合密度增加。膳食中DHA的干預(yù)可防止高飽和脂肪酸飲食對(duì)海馬和下丘腦受體密度的影響。由于海馬和下丘腦與大腦認(rèn)知功能密切有關(guān)，提示了GABAa等受體有可能介導(dǎo)了DHA增強(qiáng)大腦學(xué)習(xí)記憶的功能[40]。來自海馬體興奮性尖波(sharp waves，SPWs)被認(rèn)為顳葉癲癇患者發(fā)作的前兆。采用體外腦片灌流，發(fā)現(xiàn)在海馬切片CA1和CA3區(qū)域，DHA可以減少SPWs發(fā)生率，上述作用可以被GABA受體阻滯劑所拮抗。實(shí)驗(yàn)表明DHA可以減少小鼠海馬CA3回路的興奮性，而這種作用可能與GABA神經(jīng)系統(tǒng)的調(diào)節(jié)作用有關(guān)，提示DHA有可能通過對(duì)海馬神經(jīng)元興奮性的調(diào)節(jié)，影響大腦的學(xué)習(xí)記憶功能[41]。在大腦發(fā)育期，DHA迅速的積累對(duì)正常神經(jīng)的結(jié)構(gòu)和功能至關(guān)重要。在腦發(fā)育的關(guān)鍵時(shí)期，DHA缺乏會(huì)造成多種大腦功能障礙，包括學(xué)習(xí)記憶功能和成年后的抑郁和焦慮癥等，實(shí)驗(yàn)發(fā)現(xiàn)GABAa系統(tǒng)可能參與了這些作用[42]。此外GABA還可能介導(dǎo)了-3 PUFA對(duì)大腦的保護(hù)作用，如丙酸所造成的神經(jīng)中毒等，有利于大腦學(xué)習(xí)記憶功能的維持[43]。

在生理?xiàng)l件下膽堿能神經(jīng)元與機(jī)體的衰老密切相關(guān)。在病理?xiàng)l件下膽堿能神經(jīng)元與多種老年性神經(jīng)系統(tǒng)的疾病有關(guān)，例如阿爾茨海默病(AD)等。AD是以進(jìn)行性智能衰退為主要臨床表現(xiàn)的大腦變性疾病，俗稱老年癡呆癥。在病理特征上表現(xiàn)為老年斑、神經(jīng)元纖維纏結(jié)、海馬錐體細(xì)胞膽堿能神經(jīng)元的變性壞死。AD的發(fā)病與腦內(nèi)Aβ(β淀粉樣蛋白)異常沉淀有關(guān)。Aβ對(duì)周圍的突觸和神經(jīng)元具有毒性作用，可導(dǎo)致神經(jīng)細(xì)胞變性死亡。隨著神經(jīng)元的變性壞死，導(dǎo)致腦內(nèi)相應(yīng)的神經(jīng)遞質(zhì)水平下降，其中最主要的是乙酰膽堿(acetylcholine，Ach)。在AD患者中，腦內(nèi)的Ach的水平下降得最早和最為明顯。增加腦內(nèi)Ach的水平是目前AD藥物治療的重要方法。例如，采用膽堿酯酶抑制劑，通過抑制Ach的酶解，增加Ach的含量，增加膽堿能神經(jīng)元的傳遞功能。但這些擬膽堿類藥物，雖然能緩解患者認(rèn)知能力的下降，但并不能延緩AD病程的發(fā)展。

多巴胺能神經(jīng)元的遞質(zhì)是多巴胺(DA)主要存在于中樞神經(jīng)系統(tǒng)，包括黑質(zhì)-紋狀體系統(tǒng)、中腦邊緣和皮質(zhì)系統(tǒng)以及結(jié)節(jié)漏斗部3個(gè)部分。腦內(nèi)的DA主要由中腦黑質(zhì)產(chǎn)生，沿黑質(zhì)-紋狀體系統(tǒng)投射，在紋狀體內(nèi)儲(chǔ)存。DA神經(jīng)元投射的區(qū)域與大腦的學(xué)習(xí)記憶功能密切相關(guān)。多巴胺受體包括DA1～DA55種亞型，都是G蛋白偶聯(lián)受體。主要參與對(duì)軀體運(yùn)動(dòng)、精神情緒活動(dòng)、垂體內(nèi)分泌以及大腦的認(rèn)知功能的調(diào)節(jié)。

在中樞神經(jīng)系統(tǒng)，5-羥色胺(5-HT)能神經(jīng)元胞體主要集中于低位腦干的中縫核內(nèi)。其纖維投射分上行部分和下行部分。下行部分支配脊髓和低位腦干。上行部分的神經(jīng)元位于中縫核頭部，纖維投射到紋狀體、丘腦、小丘腦、邊緣前腦和大腦皮層等區(qū)域。5-HT在中樞神經(jīng)系統(tǒng)的主要功能是調(diào)節(jié)痛覺和鎮(zhèn)痛、精神和情緒活動(dòng)等。但值得注意的是5-HT分布的區(qū)域與大腦的學(xué)習(xí)記憶和認(rèn)知功能密切相關(guān)。5-HT的受體多而復(fù)雜，已知有5-HT1至5-HT7等多種受體，進(jìn)一步分為不同的亞型如5-HT1A、5-HT2B等，其對(duì)大腦學(xué)習(xí)記憶功能的影響已開始受到關(guān)注。

綜上所述，突觸是完成大腦功能的基礎(chǔ)，包括大腦的學(xué)習(xí)記憶功能和認(rèn)知能力。然而大腦的功能是復(fù)雜的，大腦的學(xué)習(xí)記憶功能和認(rèn)知能力受到多種精神因素的影響，例如抑郁癥、精神分裂癥和情緒失調(diào)癥、注意缺陷和多動(dòng)癥等，因此多個(gè)不同的系統(tǒng)，從不同的方面，參與了大腦學(xué)習(xí)記憶功能的調(diào)節(jié)。-3 PUFA對(duì)谷氨酸、GABA、Ach、DA和5-HT受體外，還有許多受體參與了大腦學(xué)習(xí)記憶功能的調(diào)節(jié)，包括Na+、K+、Ca2+離子通道型受體、辣椒素受體、酸通道受體和大麻素受體等，但具體作用機(jī)制并不清晰，亟待后期進(jìn)行深入研究。

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(2015-12-10 收稿)

*國家自然科學(xué)基金資助項(xiàng)目(No.31271855)；國家自然科學(xué)基金青年科學(xué)基金資助項(xiàng)目(No.31000772)；湖北省自然科學(xué)基金資助項(xiàng)目(No.2014CFB887，No.2015CFC841)，湖北省教育廳科學(xué)技術(shù)研究項(xiàng)目(No.D20141705)

R344.1

10.3870/j.issn.1672-0741.2016.06.023

劉志國，男，1963年生，教授，理學(xué)博士，E-mail：zhiguo_l@126.com

△通訊作者，Corresponding author，E-mail：liulieju@qq.com