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. This evidence concerns the gene AVP and major depressive disorder.