Microglial Alkbh5 Deficiency Alleviates Chronic Restraint Stress-Induced Depression-like Behaviors in Mice
Ao Li1,2 · Lu Han2 · Jia Guo1,2 · Na Zhang1,2 · Ranxu Liu2,3 · Jingdan Zhang2 · Xiaoheng Li2 · Zengqiang Yuan2,4 · Jinbo Cheng1,2
1 College of Life & Environmental Science, Center on Translational Neuroscience, Minzu University of China, Beijing 100081, China
2 The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing 100850, China
3 Hengyang Medical College, University of South China, Hengyang 421001, China
4 Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang 050000, China
Abstract
Depression is a common and severe neuropsychiatric disorder, and its underlying biological regulatory mechanisms remain unclear. Microglia are resident immune cells of the central nervous system (CNS) that critically mediate the occurrence and development of CNS diseases, including depression. As the most abundant RNA modification, N6-methyladenosine (m6A) regulates microglial function. However, its role and molecular mechanisms in depression remain unclear. In this study, we found that m6A levels decreased in the microglia of the chronic restraint stress (CRS)-induced depression mouse model. Among m6A modulation factors, Alkbh5, a demethylase, showed a significant increase in expression level. Therefore, we generated microglial-specific conditional Alkbh5 knockout mice and found that Alkbh5 deficiency alleviated CRS-induced depression-like behaviors. Mechanistically, microglial Alkbh5 deficiency inhibited excessive microglial activation, rescued dendritic spine loss, and regulated the vascular changes during CRS. Together, these results highlight the important role of Alkbh5 in regulating microglial function in the CRS-induced depression mouse model, providing a potential therapeutic target for depression.
Keywords
Depression; Microglia; Alkbh5; Chronic restraint stress; Vascular changes
