Xie Xiaoxian, Xu Haoshen, Shu Ruonan, Du Shulin, Fan Haidan, Zhang Mengya, Sun Lei, Zhou Jiafeng, Wang Liangliang, Li Zezhi, Anthony Daniel C
Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai 201108, China; Department of Pharmacology, University of Oxford, Mansfield Road OX1 3QT, Oxford, UK; Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, Shanghai Mental Health Center, Shanghai 201108, China.
College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China.
J Adv Res. 2025 Feb 1. doi: 10.1016/j.jare.2025.01.043.
PERIOD (PER)3 deficiency is associated with depression-like behaviors, but the underlying mechanisms remain unclear.
This study aims to elucidate the role and mechanism of PER3 in regulating depression-like behaviors in mice.
Depression-like behaviors were assessed using the sucrose preference test, tail suspension test, and forced swimming test. Metabolomic analysis was conducted on hippocampal tissues from Per3 knockout mice using chromatography-mass spectrometry. The regulatory role of PER3 on the expression of nicotinamide phosphoribosyltransferase (Nampt) was investigated through co-immunoprecipitation and chromatin immunoprecipitation assays.
Metabolomic analysis revealed that Per3 deficiency disrupts mitochondrial function, as evidenced by reduced activities of key tricarboxylic acidcycle enzymes (succinate dehydrogenase, citrate synthase, and α-ketoglutarate dehydrogenase), diminished expression of mitochondrial respiratory chain complexes I-V, and decreased nicotinamide adenine dinucleotide (NAD) levels in Per3 knockout mice. Supplementation with the NAD precursor nicotinamide rescued mitochondrial function and alleviated depression-like behaviors in Per3 knockout mice. Similar effects were observed with intraperitoneal administration of the NAMPT activator P7C3-A20, while these effects were abolished by the NAMPT inhibitor FK866. Mechanistically, PER3 was found to regulate Nampt expression by binding to E-box elements within its intronic regions in conjunction with BMAL1. This interaction enhanced NAD production, activating SIRT3 to mitigate mitochondrial dysfunction in Per3 knockout mice.
These findings uncover a novel mechanism by which PER3 ameliorates depressive behaviors through the regulation of NAMPT-controlled NAD levels and mitochondrial function, underscoring the critical role of PER3 in depression-related pathophysiology.
周期蛋白3（PER3）缺乏与抑郁样行为有关，但其潜在机制尚不清楚。
本研究旨在阐明PER3在调节小鼠抑郁样行为中的作用及机制。
采用蔗糖偏好试验、悬尾试验和强迫游泳试验评估抑郁样行为。利用色谱-质谱联用技术对Per3基因敲除小鼠的海马组织进行代谢组学分析。通过免疫共沉淀和染色质免疫沉淀试验研究PER3对烟酰胺磷酸核糖转移酶（Nampt）表达的调控作用。
代谢组学分析显示，Per3基因敲除小鼠的关键三羧酸循环酶（琥珀酸脱氢酶、柠檬酸合酶和α-酮戊二酸脱氢酶）活性降低、线粒体呼吸链复合体I-V的表达减少以及烟酰胺腺嘌呤二核苷酸（NAD）水平下降，这表明Per3缺乏会破坏线粒体功能。补充NAD前体烟酰胺可恢复Per3基因敲除小鼠的线粒体功能并减轻其抑郁样行为。腹腔注射NAMPT激活剂P7C3-A20也观察到类似效果，而NAMPT抑制剂FK866则消除了这些效果。从机制上讲，发现PER3通过与BMAL1结合，结合到Nampt内含子区域的E-box元件上，从而调节Nampt的表达。这种相互作用增强了NAD的产生，激活SIRT3以减轻Per3基因敲除小鼠的线粒体功能障碍。
这些发现揭示了一种新的机制，即PER3通过调节NAMPT控制的NAD水平和线粒体功能来改善抑郁行为，强调了PER3在抑郁症相关病理生理学中的关键作用。
