Dickkopf-1 blocks 17β-estradiol-enhanced object memory consolidation in ovariectomized female mice.

The memory-enhancing effects of 17β-estradiol (E2) depend upon rapid activation of several cell-signaling cascades within the dorsal hippocampus (DH). Among the many cell-signaling pathways that mediate memory processes, Wnt/β-catenin signaling has emerged as a potential key player because of its importance to hippocampal development and synaptic plasticity. However, whether E2 interacts with Wnt/β-catenin signaling to promote memory consolidation is unknown. Therefore, the present study examined whether Wnt/β-catenin signaling within the DH is necessary for E2-induced memory consolidation in ovariectomized mice tested in the object recognition and object placement tasks. Ovariectomized C57BL/6 mice received immediate post-training infusions of E2 or vehicle into the dorsal third ventricle plus the endogenous Wnt/β-catenin antagonist Dickkopf-1 (Dkk-1) or vehicle into the DH to assess whether the memory-enhancing effects of E2 depend on activation of Wnt/β-catenin signaling. Our results suggest that Dkk-1 blocks E2-induced memory enhancement as hypothesized, but may do so by only moderately blunting Wnt/β-catenin signaling while concurrently activating Wnt/JNK signaling. The current study provides novel insights into the mechanisms through which E2 enhances memory consolidation in the DH, as well as critical information about the mechanistic actions of Dkk-1.

Taxier LR ，Philippi SM ，Fortress AM ，Frick KM ... -  《-》

Canonical Wnt signaling is necessary for object recognition memory consolidation.

Fortress AM ，Schram SL ，Tuscher JJ ，Frick KM ... -  《-》

17β-Estradiol and Agonism of G-protein-Coupled Estrogen Receptor Enhance Hippocampal Memory via Different Cell-Signaling Mechanisms.

The ability of 17β-estradiol (E2) to enhance hippocampal object recognition and spatial memory depends on rapid activation of extracellular signal-regulated kinase (ERK) in the dorsal hippocampus (DH). Although this activation can be mediated by the intracellular estrogen receptors ERα and ERβ, little is known about the role that the membrane estrogen receptor GPER plays in regulating ERK or E2-mediated memory formation. In this study, post-training DH infusion of the GPER agonist G-1 enhanced object recognition and spatial memory in ovariectomized female mice, whereas the GPER antagonist G-15 impaired memory, suggesting that GPER activation, like E2, promotes hippocampal memory formation. However, unlike E2, G-1 did not increase ERK phosphorylation, but instead significantly increased phosphorylation of c-Jun N-terminal kinase (JNK) in the DH. Moreover, DH infusion of the JNK inhibitor SP600125 prevented G-1 from enhancing object recognition and spatial memory, but the ERK inhibitor U0126 did not. These data suggest that GPER enhances memory via different cell-signaling mechanisms than E2. This conclusion was supported by data showing that the ability of E2 to facilitate memory and activate ERK signaling was not blocked by G-15 or SP600125, which demonstrates that the memory-enhancing effects of E2 are not dependent on JNK or GPER activation in the DH. Together, these data indicate that GPER regulates memory independently from ERα and ERβ by activating JNK signaling, rather than ERK signaling. Thus, the findings suggest that GPER in the DH may not function as an estrogen receptor to regulate object recognition and spatial memory. Although 17β-estradiol has long been known to regulate memory function, the molecular mechanisms underlying estrogenic memory modulation remain largely unknown. Here, we examined whether the putative membrane estrogen receptor GPER acts like the classical estrogen receptors, ERα and ERβ, to facilitate hippocampal memory in female mice. Although GPER activation did enhance object recognition and spatial memory, it did so by activating different cell-signaling mechanisms from ERα, ERβ, or 17β-estradiol. These data indicate that 17β-estradiol and GPER independently regulate hippocampal memory, and suggest that hippocampal GPER may not function as an estrogen receptor in the dorsal hippocampus. These findings are significant because they provide novel insights about the molecular mechanisms through which 17β-estradiol modulates hippocampal memory.

Kim J ，Szinte JS ，Boulware MI ，Frick KM ... -  《-》

Astrocytic glutamate transport is essential for the memory-enhancing effects of 17β-estradiol in ovariectomized mice.

Taxier LR ，Pillerová M ，Branyan TE ，Sohrabji F ，Frick KM ... -  《-》

Chemogenetic Suppression of Medial Prefrontal-Dorsal Hippocampal Interactions Prevents Estrogenic Enhancement of Memory Consolidation in Female Mice.

Tuscher JJ ，Taxier LR ，Schalk JC ，Haertel JM ，Frick KM ... -  《eNeuro》