mTOR Inhibition ameliorates cognitive and affective deficits caused by Disc1 knockdown in adult-born dentate granule neurons.
mTOR Inhibition ameliorates cognitive and affective deficits caused by Disc1 knockdown in adult-born dentate granule neurons.
复制标题
mTOR 抑制可改善成人齿状颗粒神经元中 Disc1 敲低引起的认知和情感缺陷
DOI：
10.1016/j.neuron.2012.12.033
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发表时间：
2013-02-20
期刊：
影响因子：
16.2
通讯作者：
Silva AJ
中科院分区：
文献类型：
--
作者：
Zhou M;Li W;Huang S;Song J;Kim JY;Tian X;Kang E;Sano Y;Liu C;Balaji J;Wu S;Zhou Y;Zhou Y;Parivash SN;Ehninger D;He L;Song H;Ming GL;Silva AJ
大脑发育过程中的异常被认为会引发精神疾病及其他神经发育障碍。然而，诸如神经发生等发育过程在成人大脑的特定区域仍在持续，这些过程的紊乱可能导致神经发育障碍的相关表型。正如先前报道，我们发现，在成年后生成的齿状回（DG）神经元中特异性敲低Disc1，会导致mTOR信号增强、神经元过度兴奋以及神经元结构缺陷。敲低Disc1还会导致明显的认知和情感缺陷，而当受影响的DG神经元失活时，这些缺陷能够得到逆转。重要的是，使用一种美国食品药品监督管理局（FDA）批准的抑制剂来逆转mTOR信号的增强，既能够预防也能够治疗这些行为缺陷，即便相关的结构缺陷并未得到逆转。我们的研究结果表明，神经发育障碍中情感和认知表型的一部分，可能是由成年后生成的神经元紊乱所导致。因此，针对这一细胞群体的治疗，可能会对这些表型产生重大影响。
Abnormalities during brain development are thought to cause psychiatric illness and other neurodevelopmental disorders. However, developmental processes such as neurogenesis continue in restricted brain regions of adults, and disruptions of these processes could contribute to the phenotypes of neurodevelopmental disorders. As previously reported, we show that Disc1 knockdown specifically in adult-born dentate gyrus (DG) neurons results in increased mTOR signaling, hyper-excitability and neuronal structure deficits. Disc1 knockdown also resulted in pronounced cognitive and affective deficits, which could be reversed when the affected DG neurons were inactivated. Importantly, reversing increases in mTOR signaling with an FDA approved inhibitor, both prevented and treated these behavioral deficits, even when associated structural deficits were not reversed. Our findings suggest that a component of the affective and cognitive phenotypes in neurodevelopmental disorders may be caused by disruptions in adult-born neurons. Consequently, treatments directed at this cell population may have a significant impact on these phenotypes.
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DOI：
10.1073/pnas.0706900104
发表时间：
2007-11-13
影响因子：
11.1
作者：
Li, Weidong;Zhou, Yu;Cannon, Tyrone D.
通讯作者：
Cannon, Tyrone D.
影响因子：
56.9
作者：
Santarelli, L;Saxe, M;Hen, R
通讯作者：
Hen, R
影响因子：
16.2
作者：
Ehninger, Dan;Li, Weidong;Fox, Kevin;Stryker, Michael P.;Silva, Alcino J.
通讯作者：
Silva, Alcino J.
影响因子：
11
作者：
Camargo, L. M.;Collura, V.;Brandon, N. J.
通讯作者：
Brandon, N. J.
影响因子：
5.3
作者：
Arruda-Carvalho, Maithe;Sakaguchi, Masanori;Frankland, Paul W.
通讯作者：
Frankland, Paul W.