Estradiol-Induced Object Memory Consolidation in Middle-Aged Female Mice Requires Dorsal Hippocampal Extracellular Signal-Regulated Kinase and Phosphatidylinositol 3-Kinase Activation

Abstract

We previously demonstrated that dorsal hippocampal extracellular signal-regulated kinase (ERK) activation is necessary for 17β[beta]-estradiol (E2[E subscript 2]) to enhance novel object recognition in young ovariectomized mice (Fernandez et al., 2008). Here, we asked whether E2 [E subscript 2] has similar memory-enhancing effects in middle-aged and aged ovariectomized mice, and whether these effects depend on ERK and phosphatidylinositol 3-kinase (PI3K)/Akt activation. We first demonstrated that intracerebroventricular or intrahippocampal E2 [E subscript 2] infusion immediately after object recognition training enhanced memory consolidation in middle-aged, but not aged, females. The E2 [E subscript 2]-induced enhancement in middle-aged females was blocked by intrahippocampal inhibition of ERK or PI3K activation. Intrahippocampal or intracerebroventricular E2 [E subscript 2] infusion in middle-aged females increased phosphorylation of p42 ERK in the dorsal hippocampus 15 min, but not 5 min, after infusion, an effect that was blocked by intrahippocampal inhibition of ERK or PI3K activation. Dorsal hippocampal PI3K and Akt phosphorylation was increased 5 min after intrahippocampal or intracerebroventricular E2 [E subscript 2] infusion in middle-aged, but not aged, females. Intracerebroventricular E2 infusion also increased PI3K phosphorylation after 15 min, and this effect was blocked by intrahippocampal PI3K, but not ERK, inhibition. These data demonstrate for the first time that activation of dorsal hippocampal PI3K/Akt and ERK signaling pathways is necessary for E2 [E subscript 2] to enhance object recognition memory in middle-aged females. They also reveal that similar dorsal hippocampal signaling pathways mediate E2 [E subscript 2]-induced object recognition memory enhancement in young and middle-aged females and that the inability of E2 [E subscript 2] to activate these pathways may underlie its failure to enhance object recognition in aged females.