Mutations in the alpha3 Na+,K+-ATPase underlie a mouse model of bipolar disorder

Abstract

Event Abstract Back to Event Mutations in the alpha3 Na+,K+-ATPase underlie a mouse model of bipolar disorder Greer Kirshenbaum1*, Steven Duffy1, Martin Ralph2 and John Roder1 1 Mount Sinai Hospital, Samuel Lunenfeld Research Institute, Canada 2 University of Toronto, Department of Physiology, Canada The nonexistence of a valid animal model for Bipolar disorder (BD) has been hindering the discovery of the underlying neurobiology of the disease and the development of novel treatments. By ENU mutagenesis, my lab has created a mouse called Myshkin that has a point mutation in the alpha-3 sodium potassium ATPase pump (ATP1A3) causing haploinsufficiency. Myshkin is a compelling new mouse model of BD as it demonstrates construct validity, face validity and predictive validity. The model has construct validity as the underlying pathology of BD may involve altered Na+/K+ ATPase activity. Several studies show that tissues from BD patients have altered ion regulation, consistent with decreased function of the ATP1A3; BD tissues have elevated resting and stimulated intracellular Na+ and Ca+ as well as decreased Na+/K+ ATPase concentrations and increased Na+/K+ ATPase inhibitory ligand concentrations. Similarly, cultured cortical cells from Myshkin show a higher intracellular rise in Ca2+ and slower Ca2+ clearance than wild type cells after glutamate stimulation. Further, mutations in ATP1A1, ATP1A2 and ATP1A3 genes have been identified in BD populations. Myshkin demonstrate many symptoms of BD found in humans. Myshkin show a manic phenotype, demonstrating face validity. Bipolar patients show increased activity in the manic state and Myshkin are hyperactive in the open field, forced swim test, tail suspension test, emergence test and elevated plus maze. Bipolar patients in the manic state engage in risk taking behaviour and Myshkin also show increased risk taking behaviour in the elevated plus maze and emergence test. Consistent with mania in BD, Myshkin have significantly altered circadian rhythms. Myshkin show increased preference for sucrose indicating hyperhedonia in the sucrose preference test that is also consistent with mania. Sodium valproate and lithium carbonate are common treatments for BD in humans and alleviate many symptoms of the disease. The manic symptoms in Myshkin were attenuated by both sodium valproate and lithium carbonate indicating predictive validity of the model. There is evidence that both humans with BD and Myshkin have decreased function of the ATP1A3; Myshkin show similar symptoms as humans with BD and respond to the most effective drugs for BD. Increasing the activity of the ATP1A3 may be a useful target for new drug therapies for BD. Conference: B.R.A.I.N. platform in Physiology poster day 2009, Toronto, ON, Canada, 16 Dec - 16 Dec, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Kirshenbaum G, Duffy S, Ralph M and Roder J (2009). Mutations in the alpha3 Na+,K+-ATPase underlie a mouse model of bipolar disorder. Front. Neurosci. Conference Abstract: B.R.A.I.N. platform in Physiology poster day 2009. doi: 10.3389/conf.neuro.03.2009.17.028 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 17 Dec 2009; Published Online: 17 Dec 2009. * Correspondence: Greer Kirshenbaum, Mount Sinai Hospital, Samuel Lunenfeld Research Institute, Toronto, Canada, greershelby@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Greer Kirshenbaum Steven Duffy Martin Ralph John Roder Google Greer Kirshenbaum Steven Duffy Martin Ralph John Roder Google Scholar Greer Kirshenbaum Steven Duffy Martin Ralph John Roder PubMed Greer Kirshenbaum Steven Duffy Martin Ralph John Roder Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.