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<p>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 (m<sup>6</sup>A) regulates microglial function. However, its role and molecular mechanisms in depression remain unclear. In this study, we found that m<sup>6</sup>A levels decreased in the microglia of the chronic restraint stress (CRS)-induced depression mouse model. Among m<sup>6</sup>A modulation factors, Alkbh5, a demethylase, showed a significant increase in expression level. Therefore, we generated microglial-specific conditional <i>Alkbh5</i> knockout mice and found that Alkbh5 deficiency alleviated CRS-induced depression-like behaviors. Mechanistically, microglial <i>Alkbh5</i> 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.</p>

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Microglial Alkbh5 Deficiency Alleviates Chronic Restraint Stress-Induced Depression-like Behaviors in Mice

  • 期刊论文

  • 发表日期：

    2026年7月1日

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  • Ao Li,
  • Lu Han,
  • Jia Guo,
  • Na Zhang,
  • Ranxu Liu,
  • Jingdan Zhang,
  • Xiaoheng Li,
  • Zengqiang Yuan,
  • Jinbo Cheng

摘要

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.