McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC H4H 1R3, Canada.
Integrated Program in Neuroscience, McGill University, Montreal, QC H3A 0G4, Canada.
Int J Mol Sci. 2023 Mar 25;24(7):6220. doi: 10.3390/ijms24076220.
RNA modifications known as epitranscriptomics have emerged as a novel layer of transcriptomic regulation. Like the well-studied epigenetic modifications characterized in DNA and on histone-tails, they have been shown to regulate activity-dependent gene expression and play a vital role in shaping synaptic connections in response to external stimuli. Among the hundreds of known RNA modifications, N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotes. Through recognition of its binding proteins, m6A can regulate various aspects of mRNA metabolism and is essential for maintaining higher brain functions. Indeed, m6A is highly enriched in synapses and is involved in neuronal plasticity, learning and memory, and adult neurogenesis. m6A can also respond to environmental stimuli, suggesting an important role in linking molecular and behavioral stress. This review summarizes key findings from fields related to major depressive disorder (MDD) including stress and learning and memory, which suggest that activity-dependent m6A changes may, directly and indirectly, contribute to synaptic connectivity changes underlying MDD. Furthermore, we will highlight the roles of m6A and FTO, a m6A eraser, in the context of depressive-like behaviors. Although we have only begun to explore m6A in the context of MDD and psychiatry, elucidating a link between m6A and MDD presents a novel molecular mechanism underlying MDD pathogenesis.
RNA 修饰被称为表观转录组学，它是转录组调控的一个新层面。就像在 DNA 和组蛋白尾巴上研究得很好的表观遗传修饰一样，它们被证明可以调节活性依赖性基因表达，并在塑造对外界刺激的突触连接方面发挥重要作用。在已知的数百种 RNA 修饰中，N6-甲基腺苷（m6A）是真核生物中最丰富的 mRNA 修饰。通过识别其结合蛋白，m6A 可以调节 mRNA 代谢的各个方面，对于维持大脑的高级功能至关重要。事实上，m6A 在突触中高度富集，并参与神经元可塑性、学习和记忆以及成年神经发生。m6A 还可以对环境刺激做出反应，这表明它在将分子和行为应激联系起来方面发挥着重要作用。
这篇综述总结了与 major depressive disorder (MDD) 相关的领域的关键发现，包括应激和学习记忆，这些发现表明活性依赖性 m6A 变化可能直接和间接地导致 MDD 相关的突触连接变化。此外，我们将强调 m6A 和 FTO（一种 m6A 擦除酶）在抑郁样行为中的作用。虽然我们才刚刚开始在 MDD 和精神病学的背景下探索 m6A，但阐明 m6A 与 MDD 之间的联系为 MDD 的发病机制提供了一个新的分子机制。
