Mania-like behavior induced by genetic dysfunction of the neuron-specific Na+,K+-ATPase ?3 sodium pump.

ABSTRACT: Bipolar disorder is a debilitating psychopathology with unknown etiology. Accumulating evidence suggests the possible involvement of Na(+),K(+)-ATPase dysfunction in the pathophysiology of bipolar disorder. Here we show that Myshkin mice carrying an inactivating mutation in the neuron-specific Na(+),K(+)-ATPase ?3 subunit display a behavioral profile remarkably similar to bipolar patients in the manic state. Myshkin mice show increased Ca(2+) signaling in cultured cortical neurons and phospho-activation of extracellular signal regulated kinase (ERK) and Akt in the hippocampus. The mood-stabilizing drugs lithium and valproic acid, specific ERK inhibitor SL327, rostafuroxin, and transgenic expression of a functional Na(+),K(+)-ATPase ?3 protein rescue the mania-like phenotype of Myshkin mice. These findings establish Myshkin mice as a unique model of mania, reveal an important role for Na(+),K(+)-ATPase ?3 in the control of mania-like behavior, and identify Na(+),K(+)-ATPase ?3, its physiological regulators and downstream signal transduction pathways as putative targets for the design of new antimanic therapies.

SUBMITTER: Kirshenbaum GS 

PROVIDER: S-EPMC3207708 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature