Modulation of the aquaporin 4 (AQP4) water-regulatory channel or production of autoantibodies against this protein have been implicated in a variety of neuropsychiatric conditions, and possible mechanisms have been proposed. However, the nature of the interaction between AQP4 expression and its implications in depression remain elusive. To our knowledge, this is the first review summarising data for the involvement of AQP4 in the context of depression and related mechanisms across a wide range of experimental studies: pre-clinical (KO and wild-type), post-mortem, ex vivo, and clinical studies in depression. Overall, preclinical AQP4 wild-type studies showed that exposure to stress or inflammation, used as models of depression, decreased AQP4 protein and gene expression in various brain regions, including prefrontal cortex (PFC), choroid plexus and, especially, hippocampus. In preclinical AQP4 KO studies, AQP4 expression is necessary to prevent the effect of stress and inflammation on reduced neurogenesis and gliogenesis, and increased apoptosis and depressive-like behaviours. While in post-mortem and ex vivo studies of depression AQP4 expression was usually decreased in the hippocampus, prefrontal cortex and locus coeruleus, in clinical studies, where mRNA AQP4 expression or serum AQP4 autoantibodies were measured, there were no differences in depressed patients when compared with controls. In the future, studies should further investigate the mechanisms underlying the action of AQP4, and continue exploring if AQP4 autoantibodies are either contributing or underlying mechanisms of depression, or whether they are simply a mechanism underlying other autoimmune conditions where depression is present.
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