Metformin Activates an Atypical PKC-CBP Pathway to Promote Neurogenesis and Enhance Spatial Memory Formation
Metformin Activates an Atypical PKC-CBP Pathway to Promote Neurogenesis and Enhance Spatial Memory Formation
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DOI：
10.1016/j.stem.2012.03.016
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发表时间：
2012-07-06
期刊：
影响因子：
23.9
通讯作者：
Miller, Freda D.
中科院分区：
文献类型：
--
作者：
Wang, Jing;Gallagher, Denis;Miller, Freda D.
尽管成体神经干细胞内源性募集已被提出作为一种治疗策略，但临床上缺乏实现这一目标的方法。在这里，我们展示了广泛使用的药物二甲双胍，促进神经发生和增强空间记忆的形成。具体地说，我们证明了非典型的PKC-CBP途径对于神经前体细胞的正常发生是必不可少的，二甲双胍激活了这一途径，促进了啮齿动物和人类在培养中的神经发生。二甲双胍还以CBP依赖的方式增强成年小鼠大脑中的神经发生，这样做可以增强在水迷宫中的空间反转学习。因此，二甲双胍通过激活aPKC-CBP通路，招募神经干细胞，增强神经功能，从而为神经系统治疗提供了一种候选的药理学方法。
Although endogenous recruitment of adult neural stem cells has been proposed as a therapeutic strategy, clinical approaches for achieving this are lacking. Here, we show that metformin, a widely used drug, promotes neurogenesis and enhances spatial memory formation. Specifically, we show that an atypical PKC-CBP pathway is essential for the normal genesis of neurons from neural precursors and that metformin activates this pathway to promote rodent and human neurogenesis in culture. Metformin also enhances neurogenesis in the adult mouse brain in a CBP-dependent fashion, and in so doing enhances spatial reversal learning in the water maze. Thus, metformin, by activating an aPKC-CBP pathway, recruits neural stem cells and enhances neural function, thereby providing a candidate pharmacological approach for nervous system therapy.