SIRT3 mediates hippocampal synaptic adaptations to intermittent fasting and ameliorates deficits in APP mutant mice
SIRT3 mediates hippocampal synaptic adaptations to intermittent fasting and ameliorates deficits in APP mutant mice
复制标题
DOI：
10.1038/s41467-019-09897-1
复制
发表时间：
2019-04-23
影响因子：
16.6
通讯作者：
Mattson, Mark P.
中科院分区：
文献类型：
--
作者：
Liu, Yong;Cheng, Aiwu;Mattson, Mark P.
在癫痫和阿尔茨海默病（AD）动物模型中，间歇性食物剥夺（禁食，IF）改善情绪和认知，并保护神经元免受兴奋性毒性变性。神经元网络适应IF的机制以及这种适应如何影响神经病理过程尚不清楚。我们发现海马神经元网络通过增强GABA能张力来适应IF，这与减少焦虑样行为和改善海马依赖性记忆有关。这些神经元网络和行为适应需要线粒体蛋白脱乙酰酶SIRT3，因为它们在SIRT3缺陷型小鼠和野生型小鼠中被消除，其中SIRT3从海马神经元中选择性耗尽。在AD的App（NL）（-G-F）小鼠模型中，IF以SIRT3依赖性方式降低神经元网络过度兴奋性并改善海马突触可塑性的缺陷。这些发现证明了海马神经元中线粒体蛋白脱乙酰酶在对IF的行为和GABA能突触适应中的作用。
Intermittent food deprivation (fasting, IF) improves mood and cognition and protects neurons against excitotoxic degeneration in animal models of epilepsy and Alzheimer's disease (AD). The mechanisms by which neuronal networks adapt to IF and how such adaptations impact neuropathological processes are unknown. We show that hippocampal neuronal networks adapt to IF by enhancing GABAergic tone, which is associated with reduced anxiety-like behaviors and improved hippocampus-dependent memory. These neuronal network and behavioral adaptations require the mitochondrial protein deacetylase SIRT3 as they are abolished in SIRT3-deficient mice and wild type mice in which SIRT3 is selectively depleted from hippocampal neurons. In the App(NL)(-G-F) mouse model of AD, IF reduces neuronal network hyperexcitability and ameliorates deficits in hippocampal synaptic plasticity in a SIRT3-dependent manner. These findings demonstrate a role for a mitochondrial protein deacetylase in hippocampal neurons in behavioral and GABAergic synaptic adaptations to IF.