Stress Induced Transcriptional and Epigenetic Plasticity of Astrocytes, Microglia and Oligodendrocytes in the Pathophysiology of Depression

Major Depressive Disorder (MDD) remains a leading cause of disability worldwide, perpetuated by an incomplete understanding of its pathophysiology and the limited efficacy of conventional antidepressants. For decades, research has been dominated by neuron-centric models, particularly the monoamine hypothesis. However, a paradigm shift is underway, placing glial cells such as astrocytes, microglia, and oligodendrocytes at the centre of depression-related pathology. These cells are not merely supportive but are active participants in neuroinflammation, synaptic plasticity, neurotransmitter homeostasis, and metabolic regulation, processes profoundly disrupted in MDD. We discuss how stress-induced epigenetic modifications such as histone acetylation, methylation, and DNA methylation alter astrocytic glutamate transport, microglial inflammatory states, and oligodendrocyte-mediated myelination. Special emphasis is placed on the concept of glial transcriptional plasticity, whereby environmental adversity induces durable and cell type specific gene expression changes that underlie neuroinflammation, excitatory–inhibitory imbalance, and white matter deficits observed in MDD. By integrating findings from postmortem human tissue, single-cell omics, and stress-based animal models, this review highlights converging molecular mechanisms linking stress to glial dysfunction. We further outline how targeting glial transcriptional regulators may provide new therapeutic avenues beyond conventional monoaminergic approaches.