SIRT1 in forebrain excitatory neurons produces sexually dimorphic effects on depression-related behaviors and modulates neuronal excitability and synaptic transmission in the medial prefrontal cortex
SIRT1 in forebrain excitatory neurons produces sexually dimorphic effects on depression-related behaviors and modulates neuronal excitability and synaptic transmission in the medial prefrontal cortex
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DOI：
10.1038/s41380-019-0352-1
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发表时间：
2020-05-01
影响因子：
11
通讯作者：
Lu, Xin-Yun
中科院分区：
文献类型：
--
作者：
Lei, Yun;Wang, Jiangong;Lu, Xin-Yun
SIRT1是一种依赖NAD（+）的去乙酰化酶，是细胞代谢的关键调节因子。最近的全基因组关联研究发现SIRT1的遗传变异与重度抑郁症有关。SIRT1在大脑中广泛表达；然而，介导SIRT1作用于抑郁行为的神经元底物在很大程度上仍然未知。本研究表明，选择性删除前脑兴奋性神经元中的SIRT1会导致雄性小鼠出现抑郁样表型，而雌性小鼠则不会。成年雄性小鼠内侧前额叶皮层（mPFC）中aav - cre介导的SIRT1敲低可诱导抑郁样行为。全细胞膜片钳记录显示SIRT1的缺失降低了边缘前区mPFC V层锥体神经元的固有兴奋性和自发兴奋性突触传递。与神经元的低兴奋性一致，SIRT1敲除降低了边缘前mPFC中线粒体生物发生和动力学相关基因的密度和表达水平。当将SIRT1激活剂（SRT2104）注射到野生型小鼠的mPFC或侧脑室时，它可以逆转慢性不可预测的应激性快感缺乏和行为绝望，显示出类似抗抑郁的作用。这些结果表明，mPFC兴奋性神经元中的SIRT1是正常神经元兴奋性和突触传递所必需的，并以性别特异性的方式调节抑郁相关行为。
Sirtuin 1 (SIRT1), an NAD(+)-dependent deacetylase, is a key regulator of cellular metabolism. Recent genome-wide association studies identified genetic variants of SIRT1 linked to major depressive disorders. SIRT1 is widely expressed in the brain; however, neuronal substrates that mediate SIRT1 action on depressive behaviors remain largely unknown. Here we show that selective deletion of SIRT1 in forebrain excitatory neurons causes depression-like phenotypes in male but not female mice. AAV-Cre-mediated SIRT1 knockdown in the medial prefrontal cortex (mPFC) of adult male mice induces depressive-like behaviors. Whole-cell patch-clamp recordings demonstrate that loss of SIRT1 decreases intrinsic excitability and spontaneous excitatory synaptic transmission in layer V pyramidal neurons in the prelimbic mPFC. Consistent with neuronal hypoexcitability, SIRT1 knockout reduces mitochondrial density and expression levels of genes involved in mitochondrial biogenesis and dynamics in the prelimbic mPFC. When a SIRT1 activator (SRT2104) is injected into the mPFC or lateral ventricle of wild-type mice, it reverses chronic unpredictable stress-induced anhedonia and behavioral despair, indicating an antidepressant-like effect. These results suggest that SIRT1 in mPFC excitatory neurons is required for normal neuronal excitability and synaptic transmission and regulates depression-related behaviors in a sex-specific manner.