Investigation of the Role of the G-Protein-Coupled Estrogen Receptor in Memory Consolidation in Gonadectomized Male Mice

Estrogens are cholesterol-derived hormones that play crucial physiological and pathological roles in both sexes and across the lifespan. Many research groups have replicated the beneficial roles of 17-beta-estradiol (E2), the most potent estrogen, in memory consolidation in the past decades, even though some mechanisms are still unclear. The rapid effects of E2 in memory formation are attributed to its binding to different estrogen receptors (ER), notably the intracellular receptors ER and ER, as well as the membrane ER called G protein-coupled estrogen receptor (GPER). Previous work from our laboratory demonstrated that acute post-training infusion of E2 into the dorsal hippocampus (DH) of ovariectomized female mice enhances object recognition and spatial memory consolidation via activation of ER-alpha and ER-beta, and downstream ERK signaling (Boulware et al., 2013). Although E2 has similarly beneficial effects on memory consolidation in male mice, these effects do not depend on ERK signaling (Koss et al., 2018), suggesting sex differences in the molecular mechanisms through which E2 consolidates object memories. We have also shown that post-training DH infusion of the GPER agonist G-1 enhanced memory consolidation in ovariectomized (OVX) female mice in a manner dependent on JNK/ATF2 signaling and actin polymerization (Kim et al., 2016, 2019). Our aim in the present study was to assess the effects of bilateral DH infusion of G-1 or the GPER antagonist G15 on object recognition and spatial memory consolidation in gonadectomized (GDX) male mice. We found that immediate post-training bilateral DH infusion of G-1 enhanced memory consolidation in object placement and object recognition tasks, as previously demonstrated in OVX female mice. As in females, treatment of GDX males with G-15 impaired memory consolidation in both tasks. Interestingly, GPER activation in the DH of male GDX mice did not increase the levels of phospho-JNK or phosphor-cofilin as previously observed in female OVX mice, suggesting involvement of different signaling proteins in the effects of GPER in males. Levels of phospho-cAMP-responsive element binding protein (CREB) were elevated in the DH 30 minutes following G-1 infusion, indicating that GPER in males activates an as yet unknown mechanism that triggers CREB-mediated gene transcription. Our findings show for the first time the existence of sex differences mediating the molecular mechanisms through which GPER regulates memory. Thus, this work may open new avenues for sex-specific treatment of memory-related disorders