在5月18日即將出版的Neuron雜志上,，中國科學(xué)院上海生命科學(xué)院神經(jīng)科學(xué)研究所的段樹民教授率領(lǐng)他的學(xué)生對沉默突觸的突觸前活化機制做了新的解釋,。這也是中國科學(xué)家第一次在國際頂級期刊《神經(jīng)元》上作為封面文章發(fā)表。文章的三個REVIEW一致作出了高度評價,，并在本期雜志上專門為這篇文章做了綜述,。
沈萬華，吳蓓博士等發(fā)現(xiàn)了一類與傳統(tǒng)認識上不同的沉默突觸,。此種沉默突觸既不含NMDA受體,，也不含AMPA受體,，可以被神經(jīng)元電活動依賴的突觸前刺激快速誘導(dǎo)活化，這一快速成熟的過程是由突觸前BDNF/Cdc42信號介導(dǎo)的actin聚合而完成,。此類發(fā)現(xiàn)有助于解釋神經(jīng)元發(fā)育過程中活化的機制,，并為LTP的形成提供一個可以解釋的方向。為學(xué)習與記憶的形成和神經(jīng)環(huán)路的調(diào)節(jié)提供神經(jīng)基礎(chǔ),。
突觸前遞質(zhì)釋放裝置的發(fā)育成熟和突觸后受體的轉(zhuǎn)運是中樞神經(jīng)系統(tǒng)突觸發(fā)育過程中非常重要的兩個方面,。普遍認為，在神經(jīng)元的發(fā)育早期,，大多數(shù)突觸后膜上只含NMDA受體而不含AMPA受體,。隨著神經(jīng)系統(tǒng)的發(fā)育成熟，AMPA受體的轉(zhuǎn)運上膜后才有大量功能性突觸的產(chǎn)生,。研究者也習慣的把只含NMDA受體的突觸定義為沉默突觸（silent synapse）,。大量研究表明，AMPA受體的上膜所導(dǎo)致的沉默突觸活化機制也是LTP形成的神經(jīng)基礎(chǔ),，沉默突觸的形成和活化機制研究在神經(jīng)可塑性領(lǐng)域已經(jīng)受到了很大的重視,，闡述清楚沉默突觸的活化過程也為研究LTP相關(guān)的學(xué)習記憶提供了基本條件。雖然突觸前在沉默突觸活化過程中的作用也已經(jīng)得到重視,，但其具體的活化機制和介導(dǎo)的信號通路還不清楚,。
我們運用雙膜片鉗技術(shù)同時記錄兩個培養(yǎng)的海馬神經(jīng)元，發(fā)現(xiàn)了和傳統(tǒng)認識上不同的一類沉默突觸,，即該類突觸既沒有NMDA受體介導(dǎo)的反應(yīng),，也沒有AMPA受體介導(dǎo)的反應(yīng)。當在突觸前注入TBS后,，能快速的誘導(dǎo)此類沉默突觸轉(zhuǎn)化為功能性突觸,，并進一步揭示了這種轉(zhuǎn)變需要突觸前BDNF/Cdc42信號的參與。為進一步探索這種轉(zhuǎn)變的分子機制,，我們用FM4-64標記實驗證明了突觸前有新的功能性囊泡增加,，此過程和Cdc42介導(dǎo)的突觸前肌動蛋白微絲（actin）的聚合有關(guān)。actin-YFP熒光變化的動態(tài)觀察實驗證實了這種突觸前活性依賴的肌動蛋白聚合可以被BDNF及Cdc42信號通路的阻斷劑阻斷,。FM4-64標記的功能性囊泡與突觸前囊泡蛋白SNP的共定位實驗結(jié)果表明,，電場刺激（EFS）或BDNF誘導(dǎo)的功能性囊泡增加是因為促進了準備釋放囊泡庫（RRP）處的囊泡成熟。電鏡實驗進一步直接觀察到了電活動依賴的活性帶區(qū)的可釋放囊泡的增加,。
綜上所述,，本文發(fā)現(xiàn)了一類與傳統(tǒng)認識上不同的沉默突觸。此種沉默突觸既不含NMDA受體,，也不含AMPA受體,，可以被神經(jīng)元電活動依賴的突觸前刺激快速誘導(dǎo)活化，這一快速成熟的過程是由突觸前BDNF/Cdc42信號介導(dǎo)的actin聚合而完成,。因此,，本文揭示了神經(jīng)發(fā)育過程中沉默突觸活化的新機制,，對進一步研究突觸發(fā)育以及神經(jīng)回路的形成具有一定的指導(dǎo)意義。
同時,，段樹民教授剛剛又有一篇文章被Science接受,，在此表示熱烈的祝賀！段樹民教授實驗室在短短幾年內(nèi),，有一系列重大發(fā)現(xiàn),。
附1：
段樹民博士簡介
附2：
Volume 50 Issue 3: May 4 , 2006
Next Issue: May 18
Silent synapses are frequently found in the developing brain. Using paired patch-clamp recordings from cultured hippocampal neurons at an early development stage, Shen et al. identified nonfunctional contacts that lack both AMPA- and NMDA-mediated synaptic responses and are thus different from the conventional silent synapses containing NMDA-only responses. The authors show that presynaptic theta burst stimulation rapidly converts these contacts into functional synapses due to enhanced presynaptic glutamate release and actin polymerization induced by activation of BDNF-Cdc42 signaling at presynaptic release sites. These findings reveal a novel mechanism underlying activity-induced rapid presynaptic maturation during a critical stage of synapse formation. The context and implications of this study are discussed in a Preview by Atasoy and Kavalali.
*Wanhua Shen, *Bei Wu, Zhijun Zhang, Ying Dou, Zhi-ren Rao, Yi-ren Chen Shumin Duan, Activity-induced rapid synaptic maturation mediated by presynaptic Cdc42 signaling. Neuron, 50,401-414. May 4, 2006. [Abstract][PDF] [PDF](*Co-author).
(Note: This article was featured on this month's NEURON cover and Preview by Atasoy and Kavalali(May 4, 2006)
Summary
Maturation of presynaptic transmitter secretion machinery is a critical step in synaptogenesis. Here we report that a brief train of presynaptic action potentials rapidly converts early nonfunctional contacts between cultured hippocampal neurons into functional synapses by enhancing presynaptic glutamate release. The enhanced release was confirmed by a marked increase in the number of depolarization-induced FM4-64 puncta in the presynaptic axon. This rapid presynaptic maturation can be abolished by treatments that interfered with presynaptic BDNF and Cdc42 signaling or actin polymerization. Activation of Cdc42 by applying BDNF or bradykinin mimicked the effect of electrical activity in promoting synaptic maturation. Furthermore, activity-induced increase in presynaptic actin polymerization, as revealed by increased concentration of actin-YFP at axon boutons, was abolished by inhibiting BDNF and Cdc42 signaling. Thus, rapid presynaptic maturation induced by neuronal activity is mediated by presynaptic activation of the Cdc42 signaling pathway.
附3： 段教授實驗室最發(fā)表文章：
Xu, X., Fu, A., Ip, F., Wu, C., Duan, S., Poo, M., Yuan, X., and Ip, N. (2005) Agrin regulates growth cone turning of Xenopus spinal motoneurons. Development 132: 4309-4316.
Pan, P., Cai, Q., Lin, L., Lu, P., Duan, S., and Sheng, Z. (2005) SNAP-29-mediated Modulation of Synaptic Transmission in Cultured Hippocampal Neurons. J. Biol.Chem. 280: 25769-25779.
Li, C., Lu, J., Wu, J., Duan, S., and Poo, M. (2004) Bidirectional Modification of Presynaptic Neuronal Excitability Accompanying Spike Timing-Dependent Synaptic Plasticity. Neuron 41, 257-268.
Yang, Y., Ge, W., Chen, Y., Zhang, Z., Shen, W., Wu, C., Poo, M., and Duan, S. (2003) Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine. PNAS, 100: 15194-15199.
Zhang, J., Wang, H., Ye, C., Ge, W., Chen, Y., Jiang, Z., Wu, C., Poo, M. and Duan, S. (2003) ATP Released by Astrocytes Mediates Glutamatergic Activity-Dependent Heterosynaptic Suppression. Neuron, 40: 971-982.
Duan, S., Anderson C. M. , Keung, E. C., Chen, Y., Chen, Y., and Swanson R. A.(2003) P2X7 Receptor-Mediated Release of Excitatory Amino Acids from Astrocytes. J Neurosci, 23: 1320-1328
Wang, Z., Xu, N., Wu,CP., Duan, S., and Poo, M. (2003) Bidirectional changes in spatial dendritic integration accompanying long-term synaptic modifications. Neuron, 37: 463-472
Yuan, X., Jin, M., Xu, X., Wu, CP., Poo, M., and Duan, S.(2003) Signalling and crosstalk of Rho GTPases in mediating axon guidance. Nature Cell Biol , 5, 38 - 45 [Abstract]
Note: This paper is cited by Nature Signaling Gateway as a Featured Article.
Xiang, Y., Li, Y., Zhang, Z., Wang, S., Yuan, X.B., Wu, C., Poo, M. and Duan S., (2002) Nerve growth cones guidance mediated by G-protein-coupled receptors. Nature Neuroscience, 5, 843 - 848 [Abstract]
