Mania-like behavior induced by genetic dysfunction of the neuron-specific Na+,K+-ATPase α3 sodium pump.
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.
Samuel Lunenfeld Research Institute,  Mount Sinai Hospital, Toronto, ON,  Canada M5G 1X5.
Greer S
GS
Kirshenbaum
Steven J
SJ
Clapcote
Steven
S
Duffy
Christian R
CR
Burgess
Janne
J
Petersen
Karolina J
KJ
Jarowek
Yeni H
YH
Yücel
Miguel A
MA
Cortez
O Carter
OC
Snead
Bente
B
Vilsen
John H
JH
Peever
Martin R
MR
Ralph
John C
JC
Roder
D000818:Animals; D001714:Bipolar Disorder / Q000235:genetics* / Q000503:physiopathology; D020013:Calcium Signaling; D002478:Cells, Cultured; D002940:Circadian Rhythm; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009042:Motivation; D012201:Reward; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
D000254:Sodium-Potassium-Exchanging ATPase