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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 44; pp. 18144 - 18149
• Main Authors: Kirshenbaum, Greer S, Clapcote, Steven J, Duffy, Steven, Burgess, Christian R, Petersen, Janne, Jarowek, Karolina J, Yücel, Yeni H, Cortez, Miguel A, Snead, O. Carter III, Vilsen, Bente, Peever, John H, Ralph, Martin R, Roder, John C
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 01.11.2011; National Acad Sciences
• Subjects: Animal models; Animals; Behavioral neuroscience; Biological Sciences; Bipolar disorder; Bipolar Disorder - genetics; Bipolar Disorder - physiopathology; Brain; Calcium Signaling; Cells, Cultured; Circadian Rhythm; etiology; gene expression; hippocampus; Lithium; Medical genetics; Mice; Mice, Inbred C57BL; Mice, Transgenic; mitogen-activated protein kinase; Motivation; mutation; Neurons; pathophysiology; patients; phenotype; Protein isoforms; Reward; Signal Transduction; Sodium; sodium-potassium-exchanging ATPase; Sodium-Potassium-Exchanging ATPase - genetics; Sodium-Potassium-Exchanging ATPase - physiology; Up-Regulation; valproic acid; Vehicles
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1108416108

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 Ca2+ 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.