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0 reviewsCircular RNAs (circRNAs), characterized by their unique covalently closed circular structure, are highly stable, conserved, andexpressed in a tissue-, cell-, and developmental stage-specific manner. A lot of evidence has indicated that circRNAs play a crucialrole in diversified biological and pathological processes by sponging microRNAs (miRNAs), interacting with proteins, or beingtranslated into particular proteins, etc. Recent advancements in bioinformatics have revealed a close association between circRNAsand the development of neuropsychiatric diseases, including major depressive disorder (MDD). Increasingly, researchers emphasize1234567890();,:the significant impact of abnormal circRNA expression and its targets on the pathogenesis of MDD. However, the detailedmechanisms involved remain elusive. Research has articulated the important role of neuronal cell dysfunction in MDD. Glia cells arethe most abundant cell type in the central nervous system (CNS) and provide critical roles in MDD via intercellularinteraction–dependent pathogenic mechanisms. In this review, we extensively explore the newly identified roles of circRNAs inMDD. We summarize their novel mechanisms from cellular and molecular perspectives by deciphering how circRNAs interplaybetween neurons and neurogliocytes, followed by how circRNAs are tailored to synaptic plasticity and stress pathways under avariety of circumstances. Last, we discuss and predict their potential clinical values of diagnosis and therapy.Molecular Psychiatry;