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

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  • Greer S Kirshenbaum
  • ,
  • Steven J Clapcote
  • ,
  • Steven Duffy
  • ,
  • Christian R Burgess
  • ,
  • Janne Petersen
  • ,
  • Karolina J Jarowek
  • ,
  • Yeni H Yücel
  • ,
  • Miguel A Cortez
  • ,
  • O Carter Snead
  • ,
  • Bente Vilsen
  • John H Peever
  • ,
  • Martin R Ralph
  • ,
  • John C Roder
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-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 α3 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 α3 in the control of mania-like behavior, and identify Na(+),K(+)-ATPase α3, its physiological regulators and downstream signal transduction pathways as putative targets for the design of new antimanic therapies.
TidsskriftProceedings of the National Academy of Sciences of the United States of America
Sider (fra-til)18144-18149
Antal sider6
StatusUdgivet - 2011

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