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沉默突触研究新机制

时间:2006-05-04 14:32来源:本站原创 作者:admin 阅读:

设计:李叶菲(南京大学本科实习生)

  在最近一期的<neuron>杂志上,中国科学院上海生命科学院神经科学研究所的段树民教授率领他的学生对沉默突触的突触前活化机制做了新的解释。这也是中国科学家第一次在国际顶级期刊《神经元》上作为封面文章发表。文章的三个REVIEW一致作出了高度评价,并在本期杂志上专门为这篇文章做了综述。

  沈万华,吴蓓等发现了一类与传统认识上不同的沉默突触。此种沉默突触既不含NMDA受体,也不含AMPA受体,可以被神经元电活动依赖的突触前刺激快速诱导活化,这一快速成熟的过程是由突触前BDNF/Cdc42信号介导的actin聚合而完成。此类发现有助于解释神经元发育过程中活化的机制,并为LTP的形成提供一个可以解释的方向。为学习与记忆的形成和神经环路的调节提供神经基础。

  欣闻段树民所在的突触发育与可塑性组最近又有一篇文章被〈Science〉接受。在此表示热烈的祝贺!

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.

中文摘要:

突触前递质释放装置的发育成熟和突触后受体的转运是中枢神经系统突触发育过程中非常重要的两个方面。普遍认为,在神经元的发育早期,大多数突触后膜上只含NMDA受体而不含AMPA受体。随着神经系统的发育成熟,AMPA受体的转运上膜后才有大量功能性突触的产生。研究者也习惯的把只含NMDA受体的突触定义为沉默突触(silent synapse)。大量研究表明,AMPA受体的上膜所导致的沉默突触活化机制也是LTP形成的神经基础,沉默突触的形成和活化机制研究在神经可塑性领域已经受到了很大的重视,阐述清楚沉默突触的活化过程也为研究LTP相关的学习记忆提供了基本条件。虽然突触前在沉默突触活化过程中的作用也已经得到重视,但其具体的活化机制和介导的信号通路还不清楚。

我们运用双膜片钳技术同时记录两个培养的海马神经元,发现了和传统认识上不同的一类沉默突触,即该类突触既没有NMDA受体介导的反应,也没有AMPA受体介导的反应。当在突触前注入TBS后,能快速的诱导此类沉默突触转化为功能性突触,并进一步揭示了这种转变需要突触前BDNF/Cdc42信号的参与。为进一步探索这种转变的分子机制,我们用FM4-64标记实验证明了突触前有新的功能性囊泡增加,此过程和Cdc42介导的突触前肌动蛋白微丝(actin)的聚合有关。actin-YFP荧光变化的动态观察实验证实了这种突触前活性依赖的肌动蛋白聚合可以被BDNF及Cdc42信号通路的阻断剂阻断。FM4-64标记的功能性囊泡与突触前囊泡蛋白SNP的共定位实验结果表明,电场刺激(EFS)或BDNF诱导的功能性囊泡增加是因为促进了准备释放囊泡库(RRP)处的囊泡成熟。电镜实验进一步直接观察到了电活动依赖的活性带区的可释放囊泡的增加。

综上所述,本文发现了一类与传统认识上不同的沉默突触。此种沉默突触既不含NMDA受体,也不含AMPA受体,可以被神经元电活动依赖的突触前刺激快速诱导活化,这一快速成熟的过程是由突触前BDNF/Cdc42信号介导的actin聚合而完成。因此,本文揭示了神经发育过程中沉默突触活化的新机制,对进一步研究突触发育以及神经回路的形成具有一定的指导意义。

段树民教授简介

段教授实验室最发表文章

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]

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