Xian Zhuohang, Tian Liangjing, Yao Zhixuan, Cao Lei, Jia Zhilin, Li Gangqin
West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, China.
Department of Forensic Psychiatry, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, China.
Mol Neurobiol. 2025 May;62(5):5484-5500. doi: 10.1007/s12035-024-04614-6. Epub 2024 Nov 18.
N6-methyladenosine (m6A) is one of the most common post-transcriptional RNA modifications, which plays a critical role in various bioprocesses such as immunological processes, stress response, cell self-renewal, and proliferation. The abnormal expression of m6A-related proteins may occur in the central nervous system, affecting neurogenesis, synapse formation, brain development, learning and memory, etc. Accumulating evidence is emerging that dysregulation of m6A contributes to the initiation and progression of psychiatric disorders including depression. Until now, the specific pathogenesis of depression has not been comprehensively clarified, and further investigations are warranted. Stress, inflammation, neurogenesis, and synaptic plasticity have been implicated as possible pathophysiological mechanisms underlying depression, in which m6A is extensively involved. Considering the extensive connections between depression and neurofunction and the critical role of m6A in regulating neurological function, it has been increasingly proposed that m6A may have an important role in the pathogenesis of depression; however, the results and the specific molecular mechanisms of how m6A methylation is involved in major depressive disorder (MDD) were varied and not fully understood. In this review, we describe the underlying molecular mechanisms between m6A and depression from several aspects including inflammation, stress, neuroplasticity including neurogenesis, and brain structure, which contain the interactions of m6A with cytokines, the HPA axis, BDNF, and other biological molecules or mechanisms in detail. Finally, we summarized the perspectives for the improved understanding of the pathogenesis of depression and the development of more effective treatment approaches for this disorder.
N6-甲基腺苷（m6A）是最常见的转录后RNA修饰之一，在免疫过程、应激反应、细胞自我更新和增殖等各种生物过程中发挥着关键作用。m6A相关蛋白的异常表达可能发生在中枢神经系统，影响神经发生、突触形成、大脑发育、学习和记忆等。越来越多的证据表明，m6A的失调促成了包括抑郁症在内的精神疾病的发生和发展。到目前为止，抑郁症的具体发病机制尚未完全阐明，仍需进一步研究。应激、炎症、神经发生和突触可塑性被认为是抑郁症潜在的病理生理机制，m6A广泛参与其中。考虑到抑郁症与神经功能之间的广泛联系以及m6A在调节神经功能中的关键作用，越来越多的人提出m6A可能在抑郁症的发病机制中起重要作用；然而，m6A甲基化如何参与重度抑郁症（MDD）的结果和具体分子机制各不相同，尚未完全了解。在这篇综述中，我们从炎症、应激、包括神经发生在内的神经可塑性和脑结构等几个方面描述了m6A与抑郁症之间的潜在分子机制，其中详细包含了m6A与细胞因子、HPA轴、脑源性神经营养因子（BDNF）以及其他生物分子或机制的相互作用。最后，我们总结了对于更好地理解抑郁症发病机制以及开发更有效治疗方法的展望。
