SIRT1 is essential for normal cognitive function and synaptic plasticity.
SIRT1 is essential for normal cognitive function and synaptic plasticity.
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DOI：
10.1523/jneurosci.0027-10.2010
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发表时间：
2010-07-21
期刊：
影响因子：
--
通讯作者：
Longo VD
中科院分区：
文献类型：
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作者：
Michán S;Li Y;Chou MM;Parrella E;Ge H;Long JM;Allard JS;Lewis K;Miller M;Xu W;Mervis RF;Chen J;Guerin KI;Smith LE;McBurney MW;Sinclair DA;Baudry M;de Cabo R;Longo VD
正常认知功能的保护依赖于神经系统在细胞和分子水平上的正常表现。哺乳动物 NAD+ 依赖性脱乙酰酶 SIRT1 影响可能涉及维持大脑完整性的不同过程，例如染色质重塑、DNA 修复、细胞存活和神经发生。在这里，我们表明 SIRT1 在海马体神经元中表达，海马体是学习和记忆的关键结构。我们结合行为学和电生理学范式分析了 SIRT1 缺乏和过度表达对小鼠学习和记忆以及突触可塑性的影响。我们证明，SIRT1 的缺失会损害认知能力，包括即时记忆、经典条件反射和空间学习。此外，我们发现 SIRT1 敲除小鼠的认知缺陷与突触可塑性缺陷相关，但基础突触传递或 NMDA 受体功能没有改变。 SIRT1-KO小鼠的大脑表现出正常的形态和树突棘结构，但树突分支、分支长度和神经元树突乔木的复杂性减少。此外，在 SIRT1-KO 小鼠中还检测到 ERK1/2 磷酸化的减少以及涉及突触功能、脂质代谢和髓鞘形成的海马基因表达的改变。相比之下，大脑中 SIRT1 表达水平较高的小鼠表现出正常的突触可塑性和记忆力。我们得出结论，SIRT1 对于小鼠的正常学习、记忆和突触可塑性是不可或缺的。
Conservation of normal cognitive functions relies on the proper performance of the nervous system at the cellular and molecular level. The mammalian NAD+-dependent deacetylase, SIRT1, impacts different processes potentially involved in the maintenance of brain integrity such as chromatin remodeling, DNA repair, cell survival and neurogenesis. Here we show that SIRT1 is expressed in neurons of the hippocampus, a key structure in learning and memory. Using a combination of behavioral and electrophysiological paradigms we analyzed the effects of SIRT1 deficiency and overexpression on mouse learning and memory as well as on synaptic plasticity. We demonstrated that the absence of SIRT1 impaired cognitive abilities, including immediate memory, classical conditioning and spatial learning. In addition, we found that the cognitive deficits in SIRT1 knockout mice were associated with defects in synaptic plasticity without alterations in basal synaptic transmission or NMDA receptor function. Brains of SIRT1-KO mice exhibited normal morphology and dendritic spine structure but display a decrease in dendritic branching, branch length and complexity of neuronal dendritic arbors. Also, a decrease in ERK1/2 phosphorylation and altered expression of hippocampal genes involved in synaptic function, lipid metabolism and myelination were detected in SIRT1-KO mice. In contrast, mice with high levels of SIRT1 expression in brain exhibited regular synaptic plasticity and memory. We conclude that SIRT1 is indispensable for normal learning, memory and synaptic plasticity in mice.