The Role of G-protein Coupled Estrogen Receptor (GPER/GPR30) in Hippocampal Memory and Cell Signaling in Female Mice

The loss of estrogens at menopause significantly increases a woman\u27s risk of memory loss and Alzheimer\u27s disease because estrogens are essential trophic factors for the hippocampus. However, current hormone replacement therapies are not recommended to reduce age-related memory decline because of their adverse side effects. To develop better hormone replacement therapies, it is essential to understand the mechanisms through which estrogens regulate memory. Our laboratory has demonstrated that the ability of 17β-estradiol (E2) to enhance hippocampal memory depends on the rapid activation of extracellular-signal-regulated kinase (ERK), which occurs through activation of ERα and ERβ. The G-protein coupled estrogen receptor (GPER) is a novel membrane estrogen receptor, expressed in areas of the brain important for learning and memory such as the hippocampus. However, little is known about the role of dorsal hippocampal (DH) GPER in hippocampal memory consolidation and cell signaling. Here, the present study tested the roles of GPER in regulating hippocampal memory consolidation and cell signaling in young female mice. DH infusion of the GPER agonist, G-1, enhanced object recognition and spatial memory consolidation in ovariectomized female mice. DH infusion of the GPER antagonist, G-15, blocked the memory-enhancing effects of G-1, suggesting that GPER activation mimics the beneficial effects of E2 on hippocampal memory. Interestingly, however, G-1 did not increase ERK phosphorylation like E2, but instead significantly increased phosphorylation of the c-Jun N-terminal kinase (JNK) in the DH, suggesting that the molecular mechanisms underlying the memory-enhancing effects of GPER activation may differ from those of ERα and ERβ activation. Consistent with this notion, DH infusion of the JNK inhibitor, SP600125, blocked G-1-induced memory enhancement and JNK phosphorylation, whereas the ERK inhibitor, U0126, did not. Finally, we showed that DH infusion of SP600125 or G-15 did not prevent E2 from enhancing memory and activating ERK, demonstrating that the memory-enhancing effects of E2 are not dependent on JNK or GPER activation in the DH. These results indicate that GPER regulates memory independently from ERα and ERβ by activating JNK signaling, rather than ERK signaling. Together, the data suggest that GPER does not function as an estrogen receptor in the DH. As such, this study identifies GPER as a putative new target for reducing memory decline in menopausal women without the detrimental side effects of currently available treatment option