title: Decreased neuronal Na+, K+ -ATPase activity in Atp1a3 heterozygous mice increases susceptibility to depression-like endophenotypes by chronic variable stress.
abstract: 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.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital and Institute of Medical Science, University of Toronto, 600 University Avenue, Toronto, Ontario, Canada. greershelby@gmail.com
authors.forename: G S
authors.initials: GS
authors.lastname: Kirshenbaum
authors.forename: K
authors.initials: K
authors.lastname: Saltzman
authors.forename: B
authors.initials: B
authors.lastname: Rose
authors.forename: J
authors.initials: J
authors.lastname: Petersen
authors.forename: B
authors.initials: B
authors.lastname: Vilsen
authors.forename: J C
authors.initials: JC
authors.lastname: Roder
mesh_terms: D000818:Animals; D003863:Depression / Q000235:genetics* / Q000378:metabolism; D058068:Endophenotypes; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D051379:Mice; D023421:Models, Animal; D009474:Neurons / Q000201:enzymology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics* / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics*; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism
chemical_list: D000254:Sodium-Potassium-Exchanging ATPase