Aquaporin-4 Knockout Exacerbates Corticosterone-Induced Depression by Inhibiting Astrocyte Function and Hippocampal Neurogenesis

Aims The predominant expression of aquaporin-4 (AQP4) in the brain implies that this water channel may be involved in a range of brain disorders. This study was designed to investigate the role of AQP4 in the pathogenesis of depression, and related possible biological mechanism. Methods and Results Wild-type (AQP4(+/+)) and AQP4 knockout (AQP4(-/-)) mice were given daily subcutaneous injections of corticosterone (20mg/kg) for consecutive 21days. Forced swimming test (FST) and tail suspension test (TST) showed longer immobility times in corticosterone-treated AQP4(-/-) genotype, indicating AQP4 knockout exacerbated depressive-like behaviors in mice. Using immunohistological staining, western blot, and enzyme-linked immunosorbent assay (ELISA), we found a significant loss of astrocytes, aggravated downregulation of excitatory amino acid transporter 2 (EAAT2), synapsin-1, and glial cell line-derived neurotrophic factor (GDNF) in the hippocampus of AQP4(-/-) mice. Moreover, even less hippocampal neurogenesis was identified in corticosterone-treated AQP4(-/-) mice in vivo and hippocampus-derived adult neural stem cells (ANSCs) in vitro. Conclusions The present findings suggest AQP4 involves the pathogenesis of depression by modulating astrocytic function and adult neurogenesis, highlighting a novel profile of AQP4 as a potential target for the treatment for depression.