Rewriting the brain: m6A RNA methylation as an emerging epitranscriptomic regulator in major depressive disorder

Abstract

Activity-dependent gene regulation is fundamental to synaptic plasticity, and its disruption is increasingly recognized as a feature of major depressive disorder (MDD). Environmentally driven changes in gene expression can alter neural plasticity in corticolimbic brain regions, yet the post-transcriptional mechanisms linking environmental stress to maladaptive neuronal function remain incompletely understood. RNA epitranscriptomic regulation has recently emerged as an important layer of gene control, with N6-methyladenosine (m6A) representing the most abundant and dynamically reversible internal modification of mammalian mRNA. Widely present in the adult brain, m6A regulates RNA splicing, export, stability, localization, and translation, thereby shaping transcript fate and protein output. Although m6A RNA methylation has been studied extensively in other biological contexts, its contribution to MDD pathophysiology is only beginning to be defined. Current human evidence is primarily correlative, derived largely from bulk-tissue postmortem datasets, and should be considered hypothesis-generating until replicated in independent cohorts and validated with cell-type-resolved and mechanistic approaches. Emerging clinical and preclinical studies suggest that dysregulated m6A signaling may influence neurodevelopmental, neurocognitive, and stress-responsive pathways relevant to depression. By integrating environmental signals with transcriptomic regulation, m6A modification may represent a plausible epitranscriptomic mechanism governing synaptic plasticity in the depressed brain. In this review, we summarize the dynamic regulation of m6A RNA methylation in the brain, discuss its neurobiological functions, and critically evaluate its potential role in stress-related pathology and MDD.