Oral 1 - 1.2
1,2,3Elena Sidorova, 2Richard Logan, 1,2,3James Eubanks
1 Dept. of Physiology, University of Toronto; 2 Div. of Genetics and Development, Krembil Research Institute; 3 Institute of Medical Science, University of Toronto
The NAD+-dependent mitochondrial protein deacetylase, Sirtuin-3 (SIRT3) has been shown to govern a number of mitochondrial targets that feed forward to pathways involved in anti-oxidative defense systems, energy production, mitochondrial biogenesis and apoptosis. However, there is a large gap in our knowledge on the role that SIRT3 plays in normal physiology in vivo, as there has been limited research undertaken to examine specific behaviours in SIRT3-deficient mice. In this study, we investigated novel aspects of SIRT3 function on behaviour in adult and aged mice of both sexes by comparing wild-type to littermate SIRT3-KO mice. Using a battery of behavioural assessments, we show that both young and aged female SIRT3-KO mice display hyperlocomotor behaviour in open field arena, reduced anxiety-like behaviour in plus maze and light/dark paradigms and also show a loss of locomotor coordination on the rotarod test. This overall behavioural profile is strikingly similar to a mania-like phenotype. Furthermore our molecular studies of the cortex show an upregulation of the mTOR signaling cascade in the female SIRT3-KO mice. Indeed, recent studies show that hyperactivation of this pathway has been associated to play a role during episodes of mania. Further results show that treatment with 1mg/kg D-amphetamine, a widely used stimulant for rodent model of mania, SIRT3-KO female mice displayed significant sensitization for locomotion in the open field and lowered anxiety in the plus maze. Interestingly, SIRT3-KO male mice did not show any basal behavioural or molecular alterations, however following D-amphetamine treatment they also showed sensitization in the open field locomotion and diminished anxiety in the plus-maze. Our findings are the first to link SIRT3 with mania-like phenotype in rodents; moreover, the results suggest that sex differences in SIRT3-deficiency influence behaviour.