Aquaporin-4 Dysfunction in Depression: From Pathogenic Mechanisms to Novel Therapeutic Targeting

Depression represents a leading cause of global disability, yet its pathogenesis remains incompletely understood. This review synthesizes emerging evidence highlighting the multifaceted role of Aquaporin-4 (AQP4), the central nervous system's predominant water channel, in the pathophysiology of depression. Preclinical studies frequently report AQP4 dysregulation in depression models, characterized by reduced perivascular expression and impaired polarization in mood-relevant brain circuits. We delineate how AQP4 impairment is implicated in depression through several interconnected mechanistic pathways: (1) exacerbating glutamate excitotoxicity by disrupting astrocytic glutamate clearance; (2) impairing monoaminergic neurotransmission and synaptic plasticity; (3) potentiating neuroinflammatory cascades; (4) inducing mitochondrial functional impairment and oxidative stress; and (5) participating in hypothalamic-pituitary-adrenal (HPA) axis dysregulation by disrupting perineuronal osmotic and ionic homeostasis in response to arginine vasopressin (AVP) signaling. Furthermore, we explore the therapeutic relevance of AQP4, noting that diverse antidepressant treatments appear to partly exert their effects by modulating AQP4 expression and function. Collectively, the evidence positions AQP4 not as a solitary causative factor, but as a critical contributing component within the broader astrocyte-neuron-immune network. We therefore propose AQP4 as a promising node for therapeutic intervention, whose modulation may help counteract core pathophysiological processes in depression, offering a potential avenue for novel treatment development.