Our laboratory has demonstrated that 17␤-estradiol (E 2 ) enhances hippocampal memory consolidation via rapid activation of multiple intracellular signaling cascades, including the ERK/MAPK cascade (Fernandez et al., 2008; Fan et al., 2010). However, the receptor mechanisms responsible for these effects of E 2 remain unclear. In vitro, estrogen receptor ␣ (ER␣) signaling through metabotropic glutamate receptor 1a (mGluR1a) leads to ERK-dependent CREB phosphorylation (Boulware et al., 2005), suggesting that interactions between ERs and mGluR1a may be vital to the memory-enhancing effects of E 2 . As such, the present study tested the roles of classical estrogen receptors (ER␣ and ER␤) and mGluR1a in mediating the effects of E 2 on hippocampal memory consolidation. Dorsal hippocampal (DH) infusion of ER␣ (PPT) or ER␤ (DPN) agonists enhanced novel object recognition and object placement memory in ovariectomized female mice in an ERK-dependent manner, suggesting that these receptors influence memory by rapidly activating hippocampal cell signaling. Next, DH infusion of the mGluR1a antagonist LY367385 blocked the object and spatial memory facilitation induced by E 2 , PPT, and DPN, demonstrating that ER/mGluR1a signaling is critical for the memory-enhancing effects of E 2 . Finally, we show that ER␣, ER␤, mGluR1, and ERK all reside within specialized membrane microdomains of the DH, and that ER␣ and ER␤ physically interact with mGluR1, providing a means through which ERs may activate mGluRs and downstream signaling. Together, these findings provide the first in vivo evidence demonstrating that ER/mGluR signaling can mediate the beneficial effects of E 2 on hippocampal memory consolidation.

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.