The memory-enhancing effects of hippocampal estrogen receptor activation involve metabotropic glutamate receptor signaling.

Our laboratory has demonstrated that 17β-estradiol (E2) 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 E2 remain unclear. In vitro, estrogen receptor α (ERα) 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 E2. As such, the present study tested the roles of classical estrogen receptors (ERα and ERβ) and mGluR1a in mediating the effects of E2 on hippocampal memory consolidation. Dorsal hippocampal (DH) infusion of ERα (PPT) or ERβ (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 E2, PPT, and DPN, demonstrating that ER/mGluR1a signaling is critical for the memory-enhancing effects of E2. Finally, we show that ERα, ERβ, mGluR1, and ERK all reside within specialized membrane microdomains of the DH, and that ERα and ERβ 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 E2 on hippocampal memory consolidation.