Sex differences in memory modulation by mTORC1 activation

Abstract

The mechanistic target of rapamycin (mTOR) is a central regulator of several cellular processes that are required for learning and memory, through the mTOR complex 1 (mTORC1) signaling pathway. However, little is known about how mTORC1 signaling in the brain is affected by sex or disease. We previously reported that activation of mTORC1 by 3-benzyl-5- ((2-nitrophenoxy) methyl)–dihydrofuran-2(3H)-one (3BDO) upregulated hippocampal rRNA expression and enhanced memory on the hippocampal-dependent active place avoidance task in young wild-type (WT) male mice. Here, we set out to determine if mTORC1 activation by 3BDO could enhance or rescue learning and memory on the active place avoidance task in both male and female mice from two strains, WT and APP/PS1, a model of Alzheimer’s Disease (AD). We selected two age groups to analyze: 8–9-months-old, when plaques are established and deficits in spatial memory begin to appear in APP/PS1 mice, and 12–13-months-old, when plaques are extensive and memory is severally impaired in APP/PS1 mice. Our data showed that a single dose of 3BDO delivered systemically rescued memory in 8–9-months-old male APP/PS1 mice but did not significantly affect male WT mice at this age. Further, 3BDO improved latency during learning for 12–13-months-old male mice overall but did not impact memory at this age. Surprisingly, in female mice, we found that 3BDO impaired both learning and memory at 8–9-months-old in WT mice, while having no significant effect on 8–9-month-old APP/PS1 mice or 12–13-months-old mice of either genotype. After behavioral testing, we further analyzed the effects of 3BDO administration on mTOR expression by Western blot. In the dorsal hippocampus, we saw overall less mTOR and phosphorylated mTOR in females compared to males at 8–9-months-old, but overall more mTOR and phosphorylated mTOR in females compared to males at 12–13-months-old. These results challenge the current understanding of how mTORC1 functions in AD and provide a new avenue of research into potential therapeutics. At the same time, the opposing effects of 3BDO on males and females trained on the same learning and memory task highlight the importance of studying potential sex differences of emerging therapeutics.