Oligodendrocyte dysfunction in major depressive disorder: Mechanistic insights and emerging therapies

Major depressive disorder (MDD) is a debilitating neuropsychiatric condition characterized by complex and multifactorial pathobiology. Emerging evidence increasingly implicates oligodendrocyte (OL) dysfunction as a key pathophysiological mechanism in MDD, extending beyond their classical role in myelination to include critical contributions to neural plasticity, metabolic support, and circuit regulation. Such dysfunctions manifest primarily as myelin abnormalities and are closely associated with depression-related alterations in brain connectivity and emotional processing. Collectively, these findings provide a novel framework for understanding the cellular and molecular underpinnings of depression. This review systematically summarizes current evidence on the involvement of OLs in the pathogenesis of MDD, with particular emphasis on their interactions with neurons, astrocytes, and microglia within the central nervous system. In addition, we discuss emerging OL-targeted therapeutic strategies, including pharmacological, genetic, and environmental interventions that may promote remyelination or restore glial function. Finally, we highlight key knowledge gaps and propose future research directions aimed at clarifying the contribution of OL biology to depressive disorders and improving treatment outcomes.