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Mol Psychiatry. 2019 Jan 31. doi: 10.1038/s41380-019-0352-1. [Epub ahead of print]

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.

Lei Y1,2,3, Wang J1,2,3, Wang D3, Li C1, Liu B1,2, Fang X1,2, You J2, Guo M3, Lu XY4,5.

Author information

1
Department of Neuroscience & Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA.
2
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
3
Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, Shandong, China.
4
Department of Neuroscience & Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA. xylu@augusta.edu.
5
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. xylu@augusta.edu.

Abstract

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.

PMID:
30705425
DOI:
10.1038/s41380-019-0352-1

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