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

• Published in: Molecular psychiatry Vol. 25; no. 5; pp. 1094 - 1111
• Main Authors: Lei, Yun, Wang, Jiangong, Wang, Dan, Li, Chen, Liu, Bin, Fang, Xing, You, Jingjing, Guo, Ming, Lu, Xin-Yun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2020; Nature Publishing Group
• Subjects: 13/51; 14/28; 38/77; 38/90; 631/378; 64/60; 692/699/476/1414; 9/74; Animals; Antidepressants; Behavioral despair; Behavioral Sciences; Biological Psychology; Brain; Depression - genetics; Depression - metabolism; Depression - pathology; Depression, Mental; Depressive Disorder, Major - genetics; Depressive Disorder, Major - metabolism; Depressive Disorder, Major - pathology; Excitability; Excitatory Postsynaptic Potentials; Female; Forebrain; Genetic aspects; Genetic diversity; Genome-wide association studies; Genomes; Genomics; Hedonic response; Male; Medicine; Medicine & Public Health; Mental depression; Mental disorders; Mice; Mice, Inbred C57BL; Mitochondria; NAD; Neurons; Neurons - metabolism; Neurosciences; Pharmacotherapy; Phenotypes; Physiological aspects; Prefrontal cortex; Prefrontal Cortex - metabolism; Prefrontal Cortex - pathology; Psychiatry; Pyramidal cells; Pyramidal Cells - metabolism; Rodents; Sex Characteristics; Sex differences; Sexual dimorphism; SIRT1 protein; Sirtuin 1 - deficiency; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Synaptic Transmission; Ventricle; Ventricles (cerebral); Wang Dan
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-019-0352-1

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.