Enhancement of learning and memory after activation of cerebral Rho GTPases
Enhancement of learning and memory after activation of cerebral Rho GTPases
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DOI：
10.1073/pnas.0610059104
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发表时间：
2007-01-09
影响因子：
11.1
通讯作者：
Fiorentini, Carla
中科院分区：
文献类型：
--
作者：
Diana, Giovanni;Valentini, Giovanni;Fiorentini, Carla
树突状树的形态和连接性的调节机制取决于肌动蛋白动力学，而肌动蛋白动力学又受Rho GTP酶控制，Rho GTP酶是一个包含Rho、Rac和Cdc42亚家族的小GTP结合蛋白家族。细胞毒性坏死因子1（CNF 1）是一种来自大肠杆菌的蛋白毒素，其组成性激活Rho GTP酶，从而导致完整细胞中肌动蛋白细胞骨架的重塑。在这里，我们表明，在小鼠中CNF1诱导的大脑RhoA和Rac1活性的调制导致（i）大脑肌动蛋白细胞骨架的重排，（ii）增强神经传递和突触可塑性，（iii）改善学习和记忆在各种行为任务。这种作用持续数周，并且在用重组CNF1处理的小鼠中没有观察到，其中通过将位置866处的丝氨酸取代为半胱氨酸来消除酶活性。结果表明，学习能力可以通过神经连接的药理学操作来提高。
The mechanism whereby the morphology and connectivity of the dendritic tree is regulated depends on an actin dynamics that, in turn, is controlled by Rho GTPases, a family of small GTP-binding proteins encompassing Rho, Rac, and Cdc42 subfamilies. Cytotoxic necrotizing factor 1 (CNF1), a protein toxin from Escherichia coli, constitutively activates Rho GTPases, thus leading to remodeling of the actin cytoskeleton in intact cells. Here, we show that the modulation of cerebral RhoA and Rac1 activity induced by CNF1 in mice leads to (i) rearrangement of cerebral actin cytoskeleton, (ii) enhanced neurotransmission and synaptic plasticity, and (iii) improved learning and memory in various behavioral tasks. The effects persist for weeks and are not observed in mice treated with a recombinant CNF1, in which the enzymatic activity was abolished by substituting serine to cysteine at position 866. The results suggest that learning ability can be improved through pharmacological manipulation of neural connectivity.