Institute of Medical Science

Student Name: Dr. Greer Shelby Kirshenbaum
Supervisor’s full name and title: Dr. John C Roder, Professor in the Department of Molecular Genetics and Senior scientist at Samuel Lunenfeld Research Institute
PhD thesis (title and brief overview): The role of neuronal Na⁺, K⁺ -ATPase activity in putative psychiatric behavioral endophenotypes in mice.

In my PhD thesis I characterized the behavior and physiology of Na⁺, K⁺ -ATPase alpha 3 mutant mice. The mice which were created by ENU mutagenesis have a point mutation in the gene encoding Na⁺, K⁺ -ATPase alpha 3 which reduces function of the gene significantly.  I found the mice are a putative model for the manic phase of bipolar disorder. Mutant mice show many mania-related behaviors such as hyperactivity, impulsivity, reduced sleep, altered circadian rhythms, increased response to natural reward and increased response to amphetamine.  The mania related behaviors were reduced by the most common drugs used in the treatment of bipolar disorder, lithium and valproic acid.  In addition I found that reducing endogenous inhibition of Na⁺, K⁺ -ATPase alpha 3 increased whole brain Na⁺, K⁺ -ATPase activity and reduced mania related behavior. I used a novel compound, Rostafuroxin which binds ouabain binding and I used a genetic technique to reduce agrin which binds specifically to Na⁺, K⁺ -ATPase alpha 3.  Both of these targets may be developed into novel treatments.  

In separate studies I utilized a different Na⁺, K⁺ -ATPase alpha 3 heterozygous mutant mouse.  The mutation in this mouse did not reduce gene function as drastically as the ENU mutant.  Since stress reduces Na⁺, K⁺ -ATPase activity I applied a chronic stress paradigm and found that Na⁺, K⁺ -ATPase alpha 3 heterozygous mice showed an increase in depression related behaviors compared to wild-type littermates.

Put together my PhD studies add to literature identifying a role for reduced Na⁺, K⁺ -ATPase activity in psychiatric behavioral phenotypes and suggest that compounds that increase activity may be helpful in the treatment of mania and depression.

I am currently a postdoctoral scientist at Columbia University. I am studying how the brain encodes stress and how the brain changes following stressful experience.  My dream is to return to the University of Toronto and become a principal investigator and professor.
 

Scholarship and awards
I was funded by a Ontario Mental Health Foundation Research Studentship during my PhD. In addition I received the following awards:

2006 University of Toronto Institute of Medical Science Entrance Award  $2 500
2007 University of Toronto Institute of Medical Science Award $2 500
2007-2008 Samuel Lunenfeld Research Institute Fellowship $15 000
2007-2008 Margaret and Howard Gamble Research Grant $6 000
2008 First place University of Toronto Program in Neuroscience Poster Competition
2008 First place University of Toronto Institute of Medical Science Alan Wu Poster Competition
2008 Samuel Lunenfeld Research Institute Trainee Travel Award
2009 Ontario Mental Health Foundation Research Studentship 3 years $48 000
2009 University of Toronto Institute of Medical Science Award $2 500
2010 University of Toronto Institute of Medical Science Laidlaw Manuscript Finalist
2010 University of Toronto Program in Neuroscience Society for Neuroscience 2010 Trainee Award

Publications
Currently I have published 3 first author papers and an additional paper (see below). I have 2 additional publications currently submitted and 2 in progress.

Clapcote SJ, Duffy S, Xie G, Kirshenbaum G, Bechard AR, Rodacker Schack V, Petersen J, Sinai L, Saab BJ, Lerch JP, Minassian BA, Ackerley CA, Sled JG, Cortez MA, Henderson JT, Vilsen B, Roder JC. Mutation I810N in the alpha3 isoform of Na+,K+-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS. Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14085-90.

Kirshenbaum GS, Saltzman K, Rose B, Petersen J, Vilsen B, Roder JC.Decreased neuronal Na⁺,K⁺-ATPase activity in Atp1a3 heterozygous mice increases susceptibility to depression-like endophenotypes by chronic variable stress. Genes Brain Behav 2011 Jul;10(5):542-50.

Kirshenbaum GS, Clapcote SJ, Duffy S, Burgess CR, Petersen J, Jarowek KJ, Yücel YH, Cortez MA, Snead OC 3rd, Vilsen B, Peever JH, Ralph MR, Roder JC.^. Mania-like behavior induced by genetic dysfunction of the neuron-specific Na⁺,K⁺-ATPase a3 sodium pump. Proc Natl Acad Sci U S A  2011. 108:18144-18149.

Kirshenbaum GS, Clapcote SJ, Petersen J, Vilsen B, Ralph MR, Roder JC. Genetic suppression of agrin reduces mania-like behavior in Na(+) ,K(+) -ATPase α3 mutant mice. Genes Brain Behav. 2012 Jun;11(4):436-43

Lectures
I have been invited to talk about my PhD work at conferences and in teaching settings (see below).

1. University of Toronto Institute of Medical Science Laidlaw manuscript competition 2010 “Decreased neuronal Na⁺, K⁺-ATPase activity increases susceptibility to depression by chronic mild stress”
2. Franco-Canadian Seminar in Neuroscience at the Ontario Investment and Trade Centre. October 7 2010 “Mutation in the Na+, K+, ATPase a3 subunit underlies a mouse model of mania”
3. 50^th Annual symposium of the Canadian Association for Laboratory Animal Science May 16/17 2011. 45 minute lecture “Mutation in the Na+, K+, ATPase a3 subunit underlies a mouse model of mania”
4. Sick Children’s Hospital Psychiatry Rounds. October 6, 2011 “Atp1a3 is a putative target for mania-related and depression-related behaviour”
5. Dalhousie University November 22, 2012 “The role of reduced Na+,K+ -ATPase activity in putative psychiatric behavioural endophenotypes in mice”
6. ATP1A3 in Disease – from Mutations to Therapies ENRAH and Center for Human Genome Variation, Duke University Brussels, Belgium December 10^th-11^th, 2012. “Mania-like behavior induced by genetic dysfunction of the neuron-specific Na⁺,K⁺-ATPase a3 sodium pump”
7. Adjunct lecturer Columbia Medical School 2012-2013. Psychopharmacology and neuroscience. Course for medical postgraduate education for residents.