神經(jīng)元與神經(jīng)膠質(zhì)細(xì)胞分析解析

1、神經(jīng)元與神經(jīng)膠質(zhì)細(xì)胞,神經(jīng)生物學(xué)系 陸巍luweishmu2@yahoo.com.cn實(shí)驗(yàn)室主頁(yè)： http://202.195.176.33/jcyxy/link/sjsw200604/wwwroot/indexc.htm,神經(jīng)元的一般結(jié)構(gòu)－－細(xì)胞體,神經(jīng)元的細(xì)胞體,細(xì)胞膜 脂質(zhì)雙層，鑲嵌蛋白細(xì)胞質(zhì) 尼氏體，神經(jīng)原纖維，內(nèi)質(zhì)網(wǎng)，高爾基復(fù)合體，溶酶體，多泡體，線粒體，中心粒和纖毛，色素顆

2、粒和脂褐素細(xì)胞核,,,細(xì)胞膜,液態(tài)的脂質(zhì)雙層中鑲嵌著球形蛋白,骨架是磷脂雙分子層。蛋白質(zhì)分子以附著、鑲嵌、貫穿的形式存在于磷脂雙分子層上,細(xì)胞膜,細(xì)胞質(zhì),特征性結(jié)構(gòu)：尼氏體：光鏡下為嗜堿性小塊或小顆粒，分布與整個(gè)胞體和樹突，軸突和軸丘中沒有；電鏡下由粗面內(nèi)質(zhì)網(wǎng)、游離核糖體和多核糖體所構(gòu)成；神經(jīng)原纖維，存在與胞體與突起中，電鏡下相當(dāng)于微管、神經(jīng)絲和微絲；線粒體特征：嵴縱向排列，線粒體內(nèi)膜所圍成的腔室，其致密顆粒不常出現(xiàn)或缺如。

3、,神經(jīng)元胞體光鏡結(jié)構(gòu)，示尼氏體,細(xì)胞質(zhì),核糖體：強(qiáng)噬堿性游離型，主要合成結(jié)構(gòu)蛋白結(jié)合型，參與酶的合成單個(gè)存在時(shí)無活性，只有當(dāng)mRNA 將它串連起來并形成多核蛋白體時(shí)才具有合成蛋白質(zhì)的能力。,,高爾基器：存在于細(xì)胞核和樹突近端。由幾層扁平囊泡、大泡所構(gòu)成。小泡由光面內(nèi)質(zhì)網(wǎng)出芽更新而來，并攜帶有粗面內(nèi)質(zhì)網(wǎng)合成的多肽和蛋白質(zhì)等，故又稱轉(zhuǎn)移小泡。通過扁平囊泡的加工濃縮，然后脫落成大泡?？赡軈⑴c突觸小泡的形成和合成多肽激素的神經(jīng)分泌顆粒

4、；還可形成溶酶體,細(xì)胞質(zhì),為細(xì)胞活動(dòng)提供能量胞內(nèi)鈣的調(diào)節(jié)因素,,,線粒體,細(xì)胞核,形態(tài)核膜,,,神經(jīng)元突起,軸突樹突,Dendrite,A neuron’s dendritic tree is connected to a thousand neighbouring neurons. When one of those neurons fire, a positive or negative charge is received

5、 by one of the dendrites. The strengths of all the received charges are added together through the processes of spatial and temporal summation. Spatial summation occurs when several weak signals are converted into a sing

6、le large one, while temporal summation converts a rapid series of weak pulses from one source into one large signal .,,Dendrite,The part of the soma that does concern itself with the signal is the axon hillock. If the ag

7、gregate input is greater than the axon hillock's threshold value, then the neuron fires, and an output signal is transmitted down the axon. The strength of the output is constant, regardless of whether the input was

8、just above the threshold, or a hundred times as great. The output strength is unaffected by the many divisions in the axon; it reaches each terminal button with the same intensity it had at the axon hillock. This uniform

9、ity is critical in an analogue device such as a brain where small errors can snowball, and where error correction is more difficult than in a digital system,Dendrites,The treelike extensions of a neuron. Most neurons hav

10、e multiple dendrites, which are short and typically highly branched. Dendrites are specialised for receiving information and form synaptic contacts with the terminals of other nerve cells to allow nerve impulses to

11、be transmitted.,樹突內(nèi)的結(jié)構(gòu)與核周質(zhì)基本相似，微管是樹突最明顯的細(xì)胞器樹突側(cè)棘，是神經(jīng)元之間形成突觸的主要部位，功能尚不清 在大腦皮質(zhì)錐體細(xì)胞和小腦皮質(zhì)蒲肯野細(xì)胞的樹突上，樹突棘數(shù)量最多而明顯，一個(gè)蒲肯野細(xì)胞的樹突棘可多達(dá)10萬個(gè)以上。樹突的功能主要是接受刺激，樹突棘和樹突使神經(jīng)元的接受面大為擴(kuò)大。,,樹突,樹突,一、樹突 樹突棘(spine) 分為細(xì)

12、長(zhǎng)型或鼓槌型(drum,stick shape)，牙型(stubby shape），蘑菇型(mushroom shape)。二、是突觸后膜所在部位，也是外來沖動(dòng)傳入部位。,Function of spines,Dendritic spines are the contact sites for most excitatory synapses in the brain where they occur in vast numbers

13、, estimated to be on the order of 1014 for the human cerebral cortex. Spines are particularly associated with neurons where inputs from diverse sources converge, such as pyramidal cells in the cerebral cortex, whose dend

14、rites commonly have several thousand spines, each representing an excitatory synapse.,,What the SynapseTells the Neuron,Magee and Cook show that in pyramidal cells of the hippocampal CA1 region, excitatory synapses grow

15、 progressively stronger with distance from the cell body—almost exactly counteracting the distance-dependent signal attrition one would expect to find. The implication is that these neurons may be striving to equalize th

16、e effectiveness of their synaptic inputs, regardless of where those inputs are located.,軸丘：軸突從胞體發(fā)出時(shí)有一錐形隆起，稱軸丘。軸突起始段：長(zhǎng)約15～25μm，電鏡下見軸膜較厚， 1）膜下有電子密度致密層，2）游離多核糖體，3）微管束。無粗面內(nèi)質(zhì)網(wǎng)和核糖體，故不能合成蛋白質(zhì)，軸突成分的更新及神經(jīng)遞質(zhì)全成所需的蛋白質(zhì)和酶，是在胞體內(nèi)合成后輸送到

17、軸突及其終末的。軸突的主要功能是傳導(dǎo)神經(jīng)沖動(dòng)。神經(jīng)沖動(dòng)的傳導(dǎo)是在軸膜上進(jìn)行的，軸突起始段軸膜的電興奮性閾較胞體或樹突低得多，故此處常是神經(jīng)元發(fā)生沖動(dòng)的起始部位。,軸突,軸漿運(yùn)輸,慢速輸送—1~3mm/天，輸送多為維持軸突結(jié)構(gòu)和生長(zhǎng)有關(guān)的物質(zhì)：如微管蛋白。與軸漿流有關(guān),快速輸送—75~400mm/天，輸送多為突觸行使功能直接需要的物質(zhì)：如線粒體、酶等。與微管有關(guān),與神經(jīng)沖動(dòng)傳導(dǎo)無關(guān)，因?yàn)槌掷m(xù)用局部麻醉藥阻斷神經(jīng)沖動(dòng)的傳導(dǎo)，并不能使軸漿

18、流動(dòng)停止，其所支配的肌肉也不會(huì)發(fā)生代謝改變而萎縮。,在缺氧、氰化物毒化等情況下，神經(jīng)纖維的有氧代謝擾亂使ATP減少到50%以下時(shí)，快速軸漿流動(dòng)即停止，說明它是一種耗能過程。 有人提出與肌肉收縮滑行理論相似的假說，來解釋快速軸漿流動(dòng)。認(rèn)為囊泡等有膜的細(xì)胞器的運(yùn)輸與微管,微絲的功能有關(guān)，微管的成分與肌纖蛋白相似，上含有結(jié)合點(diǎn)和ATP，囊泡膜上有ATP酶和能與微管相附著的結(jié)合點(diǎn)；ATP酶作用于ATP，后者放出能量使微管與囊泡膜

19、發(fā)生附著結(jié)合，而后又脫離接觸，如此推動(dòng)囊泡不斷與下一個(gè)結(jié)合點(diǎn)相附著，造成囊泡等有膜 細(xì)胞器沿著微管向前推移。,目前對(duì)由軸突末梢向細(xì)胞體方向的逆向軸漿流動(dòng)了解得比較少。這種逆向流動(dòng)的速度約為快速順向運(yùn)輸速度的一半左右。有人認(rèn)為，破傷風(fēng)毒素、狂犬病病毒由外周向中樞神經(jīng)系統(tǒng)轉(zhuǎn)運(yùn)的機(jī)制，可能就是逆向軸漿流動(dòng)。 近年來，運(yùn)用辣根過氧化酶方法研究神經(jīng)纖維的發(fā)源部位，其原理也是因?yàn)槔备^氧化酶能被軸突末梢攝取，并由軸漿流動(dòng)轉(zhuǎn)運(yùn)到神經(jīng)纖

20、維的細(xì)胞體。,雙向軸突輸送示意圖,細(xì)胞骨架,微管 microtubule,直徑24-26 nm, 微管相關(guān)蛋白(microtuble associated proteins, MAPs)，包括MAP1、MAP2、Tau蛋白；不同的MAPs在細(xì)胞內(nèi)分布不同，MAP2僅存在于胞體與樹突，而Tau蛋白主要存在于軸突。Tau蛋白的過度磷酸化與阿爾茨海默病的病理性神經(jīng)原纖維纏結(jié)的形成有關(guān)。神經(jīng)細(xì)絲 直徑10－11 nm

21、微絲 microfilament,直徑6－10 nm，主要由球狀肌動(dòng)蛋白(G-actin)組成，也含有肌球蛋白(myosin)、原肌球蛋白(tropomyosin)及輔肌蛋白(α-actin),,Spine morphology and microfilaments,spine,Spine morphology consists of an expanded head connected to the dendr

22、ite shaft by a narrower neck ,but “stubby” spineslack the neck, whereas filopodia-like “headless”spines also occur, especially during development.,Spine morphology and microfilaments,This distinctive architecture depend

23、s on a specialized underlying structure of cytoskeletal filaments. In contrast to the dendritic shaft, whose cytoplasm is dominated by microtubules the spine cytoskeleton consists of microfilaments that form longitudinal

24、 bundles in core regions of the head and neck and a meshwork of fine fibers at its periphery.,Spine morphology and microfilaments,As in other cell types, these microfilaments are composed of actin, which is present throu

25、ghout the spine cytoplasm and is closely associated with the postsynaptic density (PSD) , a disk-shaped organelle attached to the postsynaptic membrane that provides a structural framework for localizing functional molec

26、ules including neurotransmitter receptors and ion channels .,Structural features of spine-bearing neurons,神經(jīng)膠質(zhì)細(xì)胞,無軸突和樹突之分，與神經(jīng)元不構(gòu)成突觸聯(lián)系約為神經(jīng)元數(shù)的10~50倍，但因體積教小，故與神經(jīng)元所占比例近似相等,除了髓鞘形成外，膠質(zhì)細(xì)胞還具有其他功能，已知：能形成神經(jīng)元遷徙和軸突生長(zhǎng)的支架神經(jīng)元用于細(xì)胞間信息

27、傳遞的神經(jīng)遞質(zhì)的攝取和代謝攝取和緩沖細(xì)胞外環(huán)境中的離子起清道夫作用，清除死亡神經(jīng)元所遺留的殘片還可能：區(qū)分開不同種類的神經(jīng)元，起神經(jīng)元間的絕緣體作用在結(jié)構(gòu)上支撐神經(jīng)元，起著其他器官中結(jié)締組織的作用起營(yíng)養(yǎng)作用，為神經(jīng)元提供機(jī)能上必需的代謝成分甚至蛋白質(zhì)參與信息的處理和記憶存儲(chǔ),神經(jīng)元至膠質(zhì)細(xì)胞的直通車,Bergles etal.在Nature上的文章可將人們對(duì)神經(jīng)元與膠質(zhì)細(xì)胞間通訊的認(rèn)識(shí)向前推進(jìn)了一大步。 以前一

28、直認(rèn)為神經(jīng)元的突觸分泌谷氨酸，擴(kuò)散到周圍，與胞膜上有谷氨酸受體的膠質(zhì)細(xì)胞發(fā)生作用。 Bergles etal.發(fā)現(xiàn)分泌谷氨酸的神經(jīng)元與一種膠質(zhì)細(xì)胞－少突膠質(zhì)前體細(xì)胞(oligodendrocyte  precursor cells OPCs)之間可直接建立突觸連接。,Bergeles etal.對(duì)海馬切片的OPC進(jìn)行膜片鉗分析，發(fā)現(xiàn)興奮性軸突可使表達(dá)AMPA受體的膠質(zhì)細(xì)胞產(chǎn)生快速電流，這種快速電流提示谷氨酸可能被釋放

29、后僅通過了象突觸間隙那么短的距離直接作用于AMPA受體上。而且從此行為來看，作用于AMPA受體的谷氨酸濃度很高，這是擴(kuò)散理論所不能解釋的。最終，他們用電鏡觀察到了軸突與OPC之間的突觸連接。 OPC是哺乳動(dòng)物少突膠質(zhì)細(xì)胞的前體，有分泌髓磷脂的重要功能。體外，OPC的谷氨酸受體的激活可引起胞內(nèi)Ca2+濃度變化并抑制OPC的增殖和成熟，然而OPC在體內(nèi)的激活機(jī)理尚不明了。,膠質(zhì)細(xì)胞的信號(hào)轉(zhuǎn)導(dǎo)？,從總體上，神經(jīng)元的功能比膠質(zhì)細(xì)胞重要，因?yàn)橹?/p>

30、有神經(jīng)元才能進(jìn)行細(xì)胞內(nèi)和細(xì)胞間的信號(hào)傳導(dǎo)。 然而，最新的證據(jù)提示，事實(shí)上膠質(zhì)細(xì)胞也可能積極地參與腦內(nèi)的信號(hào)傳導(dǎo),中樞神經(jīng)的幾種膠質(zhì)細(xì)胞（銀染法）（1）纖維性星形膠質(zhì)細(xì)胞（2）原漿性星形膠質(zhì)細(xì)胞（3）少突膠質(zhì)細(xì)胞（4）小膠質(zhì)細(xì)胞,中樞神經(jīng)系各種神經(jīng)膠質(zhì)細(xì)胞的細(xì)胞核及神經(jīng)纖維橫切（脊髓白質(zhì)，Nissl法染色）,中樞神經(jīng)系統(tǒng)的膠質(zhì)細(xì)胞,1．星形膠質(zhì)細(xì)胞 （astrocyte）是膠質(zhì)細(xì)胞中體積最大的一種，與少突膠質(zhì)細(xì)胞合

31、稱為大膠質(zhì)細(xì)胞（macroglia）。細(xì)胞呈星形，核圓形或卵圓形，較大，染色較淺。①纖維性星形膠質(zhì)細(xì)胞（fibrous astrocyte），多分布在白質(zhì)，細(xì)胞的突起細(xì)長(zhǎng)，分支較少，胞質(zhì)內(nèi)含大量膠質(zhì)絲。組成膠質(zhì)絲的蛋白質(zhì)稱膠質(zhì)原纖維酸性蛋白（glial fibrillary acidic protein,GFAP），用免疫細(xì)胞化學(xué)染色技術(shù)，能特異性地顯示這類細(xì)胞。②原漿性星形膠質(zhì)細(xì)胞（protoplasmic astrocyte），

32、多分布在灰質(zhì)，細(xì)胞的突起較短粗，分支較多，胞質(zhì)內(nèi)膠質(zhì)絲較少。星形膠質(zhì)細(xì)胞的突起伸展充填在神經(jīng)元胞體及其突起之間，起支持和分神經(jīng)元的作用。有些突起末端形成終板（end feet），附在毛細(xì)血管壁上，或附著在腦和脊髓表面形成膠質(zhì)界膜（glia limitans）,支持作用隔離與絕緣作用引導(dǎo)發(fā)育神經(jīng)元遷移屏障作用修復(fù)與再生作用免疫應(yīng)答調(diào)節(jié)神經(jīng)元功能 1）參與神經(jīng)遞質(zhì)代謝；2）維持內(nèi)環(huán)境離子成分穩(wěn)定， 3）合成和分泌神經(jīng)活性物質(zhì),星

33、形膠質(zhì)細(xì)胞功能,在銀染色標(biāo)本中，少突膠質(zhì)細(xì)胞的突起較少，但用特異性的免疫細(xì)胞化學(xué)染色，可見少突膠質(zhì)細(xì)胞的突起并不很少，而且分支也多。少突膠質(zhì)細(xì)胞的胞體較星形膠質(zhì)細(xì)胞的小，核圓，染色較深。胞質(zhì)內(nèi)膠質(zhì)絲很少，但有較多微管和其他細(xì)胞器。少突膠質(zhì)細(xì)胞分布在神經(jīng)元胞體附近和神經(jīng)纖維周圍，它的突起末端擴(kuò)展成扁平薄膜，包卷神經(jīng)元的軸突形成髓鞘，所以它是中樞神經(jīng)系統(tǒng)的髓鞘形成細(xì)胞。新近研究認(rèn)為，少突膠質(zhì)細(xì)胞還有向神經(jīng)元提供營(yíng)養(yǎng)物質(zhì)，與神經(jīng)元有共生關(guān)

34、系,少突膠質(zhì)細(xì)胞（oligodendrocyte）,,是膠質(zhì)細(xì)胞中最小的一種。胞體細(xì)長(zhǎng)或橢圓，核小，扁平或三角形，染色深。細(xì)胞的突起細(xì)長(zhǎng)有分支，表面有許多小棘突。小膠質(zhì)細(xì)胞的數(shù)量少，約占全部膠質(zhì)細(xì)胞的5%左右。中樞神經(jīng)系統(tǒng)損傷時(shí)，小膠質(zhì)細(xì)胞可轉(zhuǎn)變?yōu)榫奘杉?xì)胞，在中樞神經(jīng)系統(tǒng)受損、炎癥、變性時(shí)大量出現(xiàn)。血循環(huán)中的單核細(xì)胞亦侵入損傷區(qū)，轉(zhuǎn)變?yōu)榫奘杉?xì)胞，參與吞噬活動(dòng)。由于小膠質(zhì)細(xì)胞有吞噬功能，有人認(rèn)為它來源于血液中的單核細(xì)胞，屬單核吞噬

35、細(xì)胞系統(tǒng)。,小膠質(zhì)細(xì)胞 （microglia）,,為立方或柱形，分布在腦室及脊髓中央管的腔面，形成單層上皮，稱室管膜（ependyma）。室管膜細(xì)胞表面有許多微絨毛，有些細(xì)胞表面有纖毛。某些地方的室管膜細(xì)胞，其基底面有細(xì)長(zhǎng)的突起伸向深部，稱伸長(zhǎng)細(xì)胞（tanycyte），它可能在腦脊液與血液或神經(jīng)氈間起運(yùn)送物質(zhì)的作用。,室管膜細(xì)胞 （ependymal cell）,,周圍神經(jīng)系統(tǒng)的膠質(zhì)細(xì)胞,雪旺細(xì)胞 （Schwann cell）是周

36、圍神經(jīng)纖維的鞘細(xì)胞，它們排列成串，一個(gè)接一個(gè)地包裹著周圍神經(jīng)纖維的軸突。在有髓神經(jīng)纖維，雪旺細(xì)胞形成髓鞘，是周圍神經(jīng)系統(tǒng)的髓鞘形成細(xì)胞?？杀磉_(dá)多種神經(jīng)營(yíng)養(yǎng)因子：營(yíng)養(yǎng)，促進(jìn)突起生長(zhǎng) 細(xì)胞粘連因子：促進(jìn)軸突生長(zhǎng)、再生 胞外基質(zhì)成分：外周神經(jīng)再生,神經(jīng)細(xì)胞：所分泌生長(zhǎng)因子為雪旺細(xì)胞 必需雪旺細(xì)胞：影響神經(jīng)元生存、分化,,相互影響,At electrical s

37、ynapses, gap junctions between pre- and postsynaptic membranes permit currentto flow passively through intercellular channels. In addition to ions, other molecules that modulate synaptic function(such as ATP and second

38、messenger molecules) can diffuse through gap junctional pores. Electrical synapses synchronize electrical activity among populations of neurons.,神經(jīng)元間連接與信號(hào)傳遞位點(diǎn)----突觸 Electrical Synapse,At most interneuronal syn

39、apses, neurotransmitters are stored in synaptic vesicles and are released after synaptic vesicle fusion at the active zone (an event that is triggered by an action potential followed by a rapid influx of calcium into the

40、 presynaptic terminal). Neurotransmitter receptors and accessory molecules accumulate in the postsynaptic membrane directly opposite the active zone in a postsynaptic membrane specialization known as thepostsynaptic den

41、sity.,Interneuronal Synapse(chemical synapse),化學(xué)性突觸的結(jié)構(gòu),突觸前 囊泡, active zone突觸間隙突觸后 突觸后致密(postsynaptic density, PSD) 遞質(zhì)受體,突觸的構(gòu)造,,,,,神經(jīng)元和突觸,,,,突觸的類型根據(jù)突觸組成分類 軸-樹突觸 最普遍，見于中樞神經(jīng)系和周圍神經(jīng)節(jié) 軸-體突觸 較普遍。

42、軸-軸突觸 見于脊髓、三叉神經(jīng)脊束核、動(dòng)眼神經(jīng) 核、薄束核、楔束核、外側(cè)膝狀體和丘腦。 樹-樹突觸 見于嗅球、脊髓、丘腦和外側(cè)膝狀體。 樹-體突觸 少見。見于外側(cè)膝狀體。 樹-軸突觸 少見。見于嗅球。 體-樹突觸 少見。見于大鼠外側(cè)膝狀體、蛙視神經(jīng)。 體-體突觸 少見。見于嗅球、外側(cè)膝狀體。 體-軸突觸 少見。見于大

43、鼠、海龜?shù)男纳窠?jīng)節(jié)。,,,,幾種突觸分布,軸體突觸,軸軸突觸,軸樹突觸,軸棘突觸,軸棘突觸,軸樹突觸,軸體突觸,,,,軸-棘突觸,,,,At the mature NMJ, pre- and postsynaptic membranes areseparated by a synaptic cleft containing extracellular proteins that form the basal lamina. Synap

44、tic vesicles are clusteredat the presynaptic release site, transmitter receptors are clustered in junctional folds at the postsynaptic membrane, and glial processes surround the nerve terminal.,Neuromuscular Junction(NM

45、J),神經(jīng)遞質(zhì)Neurotransmitter Classification,Neurotransmitter Classification,Types of Neurotransmitters in CNS,Structure and MechanismIon Channel receptorsG-Protein-Coupled ReceptorsResponsesExcitatory RecetorsInhibitory

46、 Receptors,Fast Neurotransmitters in Central Nervous Sysytem,G-Protein-Coupled Receptors,G-Protein-Mediated Responses,Metabolism of Neurotransmitters,Stages in the development of interneuronal synapses.,Activity-depende

47、nt refinement of synapticconnections,Silent Synapse,Synapse with NMDA function only: no AMPA receptor; with no-function AMPA receptor---- “deaf synapse”;because these receptors require strong stimulation for activation

48、, they appear to be functionally “silent”;In early developmental stage, silent synapse is more frequently observed.,LTP mechanisms: from silence to four-lane traffic,Two synaptic delivery pathways for AMPA

49、Rs,Model Describing Synaptic Trafficking of NMDA-Rs,Mobile NMDA Receptors at Hippocampal Synapses,,Lateral Receptor Movement,Implication of Lateral Receptor Movement,其一，突觸外的NMDA和AMPA受體通過側(cè)向移位至突觸內(nèi)，可與突觸前釋放的遞質(zhì)結(jié)合并被激活，構(gòu)成興奮性

50、突觸后電流EPSCs的一部分；其二，突觸內(nèi)受體數(shù)目的變化引起突觸傳遞功效的改變是突觸可塑性的重要機(jī)制之一。以往一直認(rèn)為突觸后膜受體數(shù)目主要以胞吐和胞吞方式來調(diào)制的，而這一新發(fā)現(xiàn)表明存在于突觸外的NMDA、AMPA受體可作為受體庫(kù)，在需要時(shí)能很快通過側(cè)向移位納入突觸內(nèi)，為調(diào)節(jié)突觸后受體數(shù)目進(jìn)而改變突觸強(qiáng)度(strength)提供了一種全新的快捷的途徑，,Implication of Lateral Receptor Movement,其