The mTOR and canonical Wnt signaling pathways mediate the mnemonic effects of progesterone in the dorsal hippocampus

Abstract

Although much is known about the neural mechanisms responsible for the mnemonic effects of 17β-estradiol (E2 ), very little is understood about the mechanisms through which progesterone (P4 ) regulates memory. We previously showed that intrahippocampal infusion of P4 in ovariectomized female mice enhances object recognition (OR) memory consolidation in a manner dependent on activation of dorsal hippocampal ERK and mTOR signaling. However, the role of specific progesterone receptors (PRs) in mediating the effects of progesterone on memory consolidation and hippocampal cell signaling are unknown. Therefore, the goals of this study were to investigate the roles of membrane-associated and intracellular PRs in mediating hippocampal memory consolidation, and identify downstream cell signaling pathways activated by PRs. Membrane-associated PRs were targeted using bovine serum albumin-conjugated progesterone (BSA-P), and intracellular PRs (PR-A, PR-B) were targeted using the intracellular PR agonist R5020. Immediately after OR training, ovariectomized mice received bilateral dorsal hippocampal infusion of vehicle, P4 , BSA-P, or R5020. OR memory consolidation was enhanced by P4 , BSA-P, and R5020. However, only P4 and BSA-P activated ERK and mTOR signaling. Furthermore, dorsal hippocampal infusion of the ERK inhibitor U0126 blocked the memory-enhancing effects of BSA-P, but not R5020. The intracellular PR antagonist RU486 blocked the memory-enhancing effects of R5020, but not BSA-P. Interestingly, P4 robustly activated canonical Wnt signaling in the dorsal hippocampus, which is consistent with our recent findings that canonical Wnt signaling is necessary for OR memory consolidation. R5020, but not BSA-P, also elicited a modest increase in canonical Wnt signaling. Collectively, these data suggest that activation of ERK signaling is necessary for membrane-associated PRs to enhance OR, and indicate a role for canonical Wnt signaling in the memory-enhancing effects of intracellular PRs. This study provides the first evidence that membrane and intracellular PRs may employ different molecular mechanisms to enhance hippocampal memory.

Rapid nongenomic modulation by neurosteroids of dendritic spines in the hippocampus: Androgen, oestrogen and corticosteroid

“…Concerning PROG effects on cognition, intrahippocampal infusion of PROG in OVX female mice enhanced object recognition memory consolidation and very rapid MAPK phosphorylation (approximately 5 minutes) was involved in this enhancement process …”

The evolving role of dendritic spines and memory: Interaction(s) with estradiol

“…Recent studies by Frick and co-workers (reviewed in Frick, 2012) have shown that direct infusion of estradiol into the dorsal hippocampus is sufficient to rapidly enhance object and place memory consolidation in mice and that this effect is associated with rapid activation, within 5 min, of NMDA receptors as well as multiple upstream and downstream cell signaling pathways including those contributing to spine formation such as the extracellular signal-regulated kinase/mitogen activated protein kinase (ERK/MAPK) pathway, cyclic AMP response element binding protein (CREB), and activation of the mammalian target of rapamycin (mTOR) protein synthesis pathway (Fortress and Frick, 2013; Fortress and Frick, 2014; Luine and Frankfurt, 2013). Moreover, memory consolidation can be blocked by inhibition of these pathways (Fortress and Frick, 2013; Fortress and Frick 2014).…”

“…Moreover, memory consolidation can be blocked by inhibition of these pathways (Fortress and Frick, 2013; Fortress and Frick 2014). Thus, it was of interest to investigate whether bilateral infusion of 5 ug of 17β-estradiol-cyclodextrin, which does not pass through cell membranes, directly into the hippocampus, would also increase spine density.…”

Trajectories and phenotypes with estrogen exposures across the lifespan: What does Goldilocks have to do with it?

“…However, there are many studies showing that progesterone can enhance some cognitive measures in rodents, mostly in the realm of non-spatial memory (Frye et al, 2007; Frye and Walf, 2008; Harburger et al, 2008; Lewis et al, 2008; Orr et al, 2009). The mechanisms of both the detrimental and enhancing effects of progestogens are currently being deciphered in the field, and the work in this area is noteworthy and convincing (Braden et al, 2011, 2010; Fortress et al, 2014; Harburger et al, 2009; Orr et al, 2012; for review see: Singh and Su, 2013a, 2013b). The disconnect between the efficacious and detrimental effects of progestogens on the brain and cognition have yet to be unraveled; this will be a critical factor to consider when designing effective hormone therapies since estrogens and progestogens will need to be combined in many clinical cases.…”