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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

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Mania-like behavior induced by genetic dysfunction of the neuron-specific Na+,K+-ATPase α3 sodium pump.

Kirshenbaum Greer S GS   Clapcote Steven J SJ   Duffy Steven S   Burgess Christian R CR   Petersen Janne J   Jarowek Karolina J KJ   Yücel Yeni H YH   Cortez Miguel A MA   Snead O Carter OC   Vilsen Bente B   Peever John H JH   Ralph Martin R MR   Roder John C JC  

Proceedings of the National Academy of Sciences of the United States of America 20111024 44


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 α3 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-ac  ...[more]

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