Abstract

NAD+dependent deacetylase, SIRT3 is a bona fide mitochondrial metabolic stress sensor. It has been linked to the regulation of the mitochondrial acetylome and activation of several metabolic enzymes (e.g., MnSOD) to protect mitochondrial function and redox homeostasis, which are vital for survival, excitability and synaptic signaling of neurons mediating short and long term memory formation as well as retention. The goal of the current study was to determine the consequences of SIRT3 deletion on hippocampal-dependent behavioral tests (Y-maze, Crawley’s Sociability and Morris Water Maze) in 18-months old male and female Sirt3+/+and Sirt3-/-mice. Our results demonstrated that both Sirt3+/+and Sirt3-/- male mice displayed significant exploration bias for the novel arm compared to the start and familiar arms in Y-maze test, while Sirt3+/+and Sirt3-/-females failed to distinguish between the novel and start arms, suggesting female mice are more prone to hippocampal dependent short term memory loss independent of SIRT3 function. Crawley’s Sociability tests also showed both Sirt3+/+and Sirt3-/-female mice demonstrated impaired sociability. However, only Sirt3-/-females presented impaired social novelty. There were no sociability or social novelty impairments in male mice from both genetic backgrounds. Finally, hippocampal-dependent spatial learning and long-term memory were assessed via the Morris Water Maze. Both female and male Sirt3-/- mice demonstrated impaired spatial memory retention implying that SIRT3 plays a role in long term memory function.We are currently examining changes in glutamate receptor subunits and pre/post-synaptic marker gene expression as well as Sholl analysis to determine changes to the dendritic arborization. We will also present the mitochondrial function data as well as activity of mitochondrial enzymes which have shown to be SIRT3 deacetylation targets to establish a link between SIRT3 mediated mitochondrial redox homeostasis and cognition.

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