Attenuation of mania-like behavior in Na(+),K(+)-ATPase α3 mutant mice by prospective therapies for bipolar disorder: melatonin and exercise.

Bipolar disorder is a neuropsychiatric disease characterized by states of mania with or without depression. Pharmacological treatments can be inadequate at regulating mood for many individuals. Melatonin therapy and aerobic exercise are independent prospective therapies for bipolar disorder that have shown potential as mood stabilizers in humans. Myshkin mice (Myk/+) carry a heterozygous missense mutation in the neuronal Na(+),K(+)-ATPase α3 and model mania-related symptoms of bipolar disorder including increased activity, risk-taking behavior and reductions in sleep. One cohort of Myk/+ and wild-type littermates (+/+) was treated with melatonin and a separate cohort was treated with voluntary exercise. Mania-related behavior was assessed in both cohorts. The effect of melatonin on sleep and the effect of exercise on brain-derived neurotrophic factor (BDNF) expression in the hippocampus were assayed. Melatonin and voluntary wheel running were both effective at reducing mania-related behavior in Myk/+ but did not affect behavior in +/+. Melatonin increased sleep in Myk/+ and did not change sleep in +/+. Myk/+ showed higher baseline levels of BDNF protein in the hippocampus than +/+. Exercise increased BDNF protein in +/+ hippocampus, while it did not significantly affect BDNF levels in Myk/+ hippocampus. These findings support initial studies in humans indicating that melatonin and exercise are useful independent adjunct therapies for bipolar disorder. Their effects on mood regulation should be further examined in randomized clinical trials. Our results also suggest that hippocampal BDNF may not mediate the effects of exercise on mania-related behavior in the Myk/+ model of mania.

Genetic suppression of agrin reduces mania-like behavior in Na+ , K+ -ATPase α3 mutant mice.

Myshkin mice heterozygous for an inactivating mutation in the neuron-specific Na(+) ,K(+) -ATPase α3 isoform show behavior analogous to mania, including an abnormal endogenous circadian period. Agrin is a proteoglycan implicated as a regulator of synapses that has been proposed to inhibit activity of Na(+) ,K(+) -ATPase α3. We examined whether the mania-related behavior of Myshkin mice could be rescued by a reduction in the expression of agrin through genetic knockout. The suppression of agrin reduced hyperambulation and holeboard exploration, restored anxiety-like behavior (or reduced risk-taking behavior), improved prepulse inhibition and shortened the circadian period. Hence, agrin is important for regulating mania-like behavior and circadian rhythms. In Myshkin mice, the suppression of agrin increased brain Na(+) ,K(+) -ATPase activity by 11 ± 4%, whereas no effect on Na(+) ,K(+) -ATPase activity was detected when agrin was suppressed in mice without the Myshkin mutation. These results introduce agrin as a potential therapeutic target for the treatment of mania and other neurological disorders associated with reduced Na(+) ,K(+) -ATPase activity and neuronal hyperexcitability.

Decreased neuronal Na+, K+ -ATPase activity in Atp1a3 heterozygous mice increases susceptibility to depression-like endophenotypes by chronic variable stress.

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.