Unipolar depression and bipolar depression are prevalent and debilitating diseases in need of effective novel treatments. It is becoming increasingly evident that depressive disorders manifest from a combination of inherited susceptibility genes and environmental stress. Genetic mutations resulting in decreased neuronal Na(+) ,K(+) -ATPase (sodium-potassium adenosine triphosphatase) activity may put individuals at risk for depression given that decreased Na(+) ,K(+) -ATPase activity is observed in depressive disorders and animal models of depression. Here, we show that Na(+) ,K(+) -ATPase α3 heterozygous mice (Atp1a3(+/-) ), with 15% reduced neuronal Na(+) ,K(+) -ATPase activity, are vulnerable to develop increased depression-like endophenotypes in a chronic variable stress (CVS) paradigm compared to wild-type littermates (Atp1a3(+/+) ). In Atp1a3(+/+) mice CVS did not decrease Na(+) ,K(+) -ATPase activity, however led to despair-like behavior in the tail suspension test (TST), anhedonia in a sucrose preference test and a minimal decrease in sociability, whereas in Atp1a3(+/-) mice CVS decreased neuronal Na(+) ,K(+) -ATPase activity to 33% of wild-type levels, induced despair-like behavior in the TST, anhedonia in a sucrose preference test, anxiety in the elevated plus maze, a memory deficit in a novel object recognition task and sociability deficits in a social interaction test. We found that a mutation that decreases neuronal Na(+) ,K(+) -ATPase activity interacts with stress to exacerbate depression. Furthermore, we observed an interesting correlation between Na(+) ,K(+) -ATPase activity and mood that may relate to both unipolar depression and bipolar disorder. Pharmaceuticals that increase Na(+) ,K(+) -ATPase activity or block endogenous Na(+) , K(+) -ATPase inhibition may provide effective treatment for depressive disorders and preclude depression in susceptible individuals.
© 2011 The Authors. Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.