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

Abstract

The ability of 17␤-estradiol (E 2 ) 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 ER␣ and ER␤, little is known about the role that the membrane estrogen receptor GPER plays in regulating ERK or E 2 -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 E 2 , promotes hippocampal memory formation. However, unlike E 2 , 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 E 2 . This conclusion was supported by data showing that the ability of E 2 to facilitate memory and activate ERK signaling was not blocked by G-15 or SP600125, which demonstrates that the memory-enhancing effects of E 2 are not dependent on JNK or GPER activation in the DH. Together, these data indicate that GPER regulates memory independently from ER␣ and ER␤ 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.

Why estrogens matter for behavior and brain health

“…In contrast, the GPER antagonist G-15 impairs spatial working memory in ovariectomized rats (Hammond et al, 2012). Consistent with these findings, post-training dorsal hippocampus or ICV infusion of G-1 enhances, whereas G-15 impairs, object recognition and object location memory consolidation (Kim et al, 2016). Unlike 17β-estradiol, however, G-1 does not increase ERK, PI3K, or Akt phosphorylation in the dorsal hippocampus, but rather increases activation of the c-Jun N-terminal Kinase (JNK) signaling pathway (Kim et al, 2016).…”

Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice

“…A 24-hour delay was used to determine whether letrozole could block the memory-enhancing effects of E 2 on OP memory consolidation. At this time point, E 2 -infused, but not vehicle-infused, mice spend more time than chance with the moved object and E 2 -infused mice spend significantly more time with the moved object than vehicle-infused mice (Boulware et al, 2013; Kim, 2016). …”

“…A 48-hour delay was used to measure whether letrozole blocked the memory-enhancing effects of E 2 because vehicle-infused females show impaired OR memory consolidation, whereas E 2 -infused females show intact OR memory consolidation, at this time point (Fortress et al, 2013, Boulware et al, 2013). Moreover, E 2 -infused females spend significantly more time with the novel object than vehicle-infused females 48 hours after infusion (Kim, 2016). Because most mice inherently prefer novelty, those that remember the training objects spend more time than chance (15 sec) exploring the novel object during testing.…”

Intracellular GPCRs Play Key Roles in Synaptic Plasticity

“…Interestingly, estrogen effects via ERα and ERβ resulted in ERK1/2 activation whereas Kim et al, found that GPER activation led to phosphorylation of JNK. Infusion of a JNK inhibitor blocked G-1 enhanced object recognition whereas ERK inhibition did not (117). Taken together these experiments underscore the diversity of signaling mechanisms associated with hippocampal memory formation and further emphasize that a single ligand, in this case estrogen, can affect many pathways independently to regulate learning and memory.…”