JBC：科学家阐明大脑产生记忆力的分子机制

  当我们制造记忆时，大脑中的神经元就会伸出“细丝”同附近的神经元形成电化学连接；近日一篇发表于国际杂志Journal of Biological Chemistry上的研究论文中，来自范德堡大学的研究人员通过研究在分子和细胞水平上揭示了记忆形成过程中神经元间的连接。
  研究者表达，我们通过进行一系列实验发现，来自神经元的纤丝会制造树突棘(dendritic spines)，而负责调节细胞迁移及吸附的一种名为Asef2的特殊信号蛋白在树突棘的形成过程中扮演着重要角色，Asef2蛋白和自闭症、酒精依赖及抑郁症的发病直接相关。Webb教授说道，树突棘的改变和许多神经变性及发育性障碍直接相关，比如自闭症、阿尔兹海默氏症以及唐氏症；然而树突棘的形成和维护是一种非常复杂的过程，需要我们去深入地理解。
  机体中的神经元可以在大脑中产生两种类型的迂回长纤维，即树突和轴突，轴突可以可以通过机体的一个神经元向另一个神经元的树突传递电化学信号，而树突则会接收信号并将其传递给机体，这就是机体神经元间的交流方式。在等待接收信号的过程中，树突会持续性地产生名为丝状假足的较小复杂的纤丝，其可以从树突表面伸出，并且在细胞间摇摆来寻找轴突；与此同时研究者认为轴突可以分泌未知的化学物来吸引丝状假足，当树突的纤丝同轴突接触后，其就会开始吸附并且发育形成树突棘，从而形成树突和轴突间的连接，这种连接是大脑记忆形成和储存的基础。
  自闭症患者大脑中往往会存在许多不成熟的树突棘，其并没有同轴突进行合适的连接来形成新的突触接头，同时树突棘的减少也是阿尔兹海默氏症发病的早期特点，这或许可以帮助解释为何患阿尔兹海默氏症的个体往往会很难形成记忆；树突棘的形成是通过肌动蛋白来驱动的，肌动蛋白可以产生微丝，其同时也是细胞骨架的组成结构，研究者表示，Asef2蛋白可以通过激活一种名为Rac蛋白来促进树突棘和突触的形成，Rac可以调节肌动蛋白的活性，同时另外一种名为树突棘素的蛋白可以补充Asef2并且引导其进入特殊的树突棘。
  最后研究者表示，本文研究由NIH等机构提供资助，下一步我们将寻找可以恢复大脑中树突棘的药物，从而来有效改善个体的大脑功能及其记忆力的形成。（转化医学网360zhyx.com）
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转化医学网推荐的原文摘要：

The Guanine Nucleotide Exchange Factor (GEF) Asef2 Promotes Dendritic Spine Formation via Rac Activation and Spinophilin-dependent Targeting*
JBC      doi: 10.1074/jbc.M114.605543
J. Corey Evans‡, Cristina M. Robinson‡1, Mingjian Shi‡ and Donna J. Webb‡,§2
Dendritic spines are actin-rich protrusions that establish excitatory synaptic contacts with surrounding neurons. Reorganization of the actin cytoskeleton is critical for the development and plasticity of dendritic spines, which is the basis for learning and memory. Rho family GTPases are emerging as important modulators of spines and synapses, predominantly through their ability to regulate actin dynamics. Much less is known, however, about the function of guanine nucleotide exchange factors (GEFs), which activate these GTPases, in spine and synapse development. In this study we show that the Rho family GEF Asef2 is found at synaptic sites, where it promotes dendritic spine and synapse formation. Knockdown of endogenous Asef2 with shRNAs impairs spine and synapse formation, whereas exogenous expression of Asef2 causes an increase in spine and synapse density. This effect of Asef2 on spines and synapses is abrogated by expression of GEF activity-deficient Asef2 mutants or by knockdown of Rac, suggesting that Asef2-Rac signaling mediates spine development. Because Asef2 interacts with the F-actin-binding protein spinophilin, which localizes to spines, we investigated the role of spinophilin in Asef2-promoted spine formation. Spinophilin recruits Asef2 to spines, and knockdown of spinophilin hinders spine and synapse formation in Asef2-expressing neurons. Furthermore, inhibition of N-methyl-D-aspartate receptor (NMDA) activity blocks spinophilin-mediated localization of Asef2 to spines. These results collectively point to spinophilin-Asef2-Rac signaling as a novel mechanism for the development of dendritic spines and synapses.