Role of astrocyte in neuroinflammation-induced loss in neuroplasticity and subsequent onset of depression: A systematic review.

Abstract

Major depressive disorder (MDD) is a complex psychiatric condition increasingly linked to chronic neuroinflammation, particularly in the context of aging, stress, and systemic comorbidities. While microglia have traditionally been the focus of neuroimmune studies, growing evidence highlights astrocytes as central regulators in the pathogenesis of MDD. This review synthesizes current findings on the multifaceted roles of astrocytes in neuroplasticity, neurotransmission, metabolic support, and blood-brain barrier regulation. It explores how astrocyte reactivity and the release of pro-inflammatory cytokines are often triggered by psychosocial stress, aging, and peripheral immune activation and contribute to synaptic dysfunction and cognitive impairment. The review also examines the bidirectional crosstalk between astrocytes and microglia, astrocytic calcium signaling, epigenetic modulation via histone lactylation, and metabolic pathways involving lactate. Special attention is given to the region-specific and phenotype-dependent responses of astrocytes, as well as their influence on the onset and maintenance of depressive symptoms. Additionally, therapeutic strategies targeting astrocyte-mediated pathways, including anti-inflammatory agents, metabolic modulators, repetitive transcranial magnetic stimulation, and inflammasome inhibitors, are discussed. Finally, methodological challenges and future research directions are outlined, emphasizing the need for precision medicine approaches in developing astrocyte-targeted interventions for MDD.