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Previous work from our laboratory has shown that the ability of estradiol to enhance object memory consolidation in young ovariectomized mice is dependent on dorsal hippocampal activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway [Fernandez SM, Lewis MC, Pechenino AS, Harburger LL, Orr PT, Gresack JE, Schafe GE, Frick KM (2008) Estradiol-induced enhancement of object memory consolidation involves hippocampal extracellular signal-regulated kinase activation and membrane-bound estrogen receptors. J Neurosci 28:8660-8667]. However, it is unclear if estradiol modulates memory or ERK activation similarly in the presence of progesterone. Therefore, the present study investigated effects of combined estradiol and progesterone treatment on object memory consolidation and dorsal hippocampal ERK activation in young ovariectomized C57BL/6 mice. Object memory was tested in a novel object recognition task. Immediately after training, mice received intraperiotoneal (i.p.) injections of vehicle, 17beta-estradiol (E(2); 0.2 mg/kg), or E(2) plus 5, 10, or 20 mg/kg progesterone (P). Forty-eight hours later, mice receiving E(2) alone or E(2) plus 10 or 20 mg/kg P exhibited significantly enhanced memory for the novel object relative to chance, whereas those receiving vehicle or E(2) plus 5 mg/kg P spent no more time than chance with the novel object. Two weeks later, ERK phosphorylation was measured in the dorsal hippocampus 1 h after i.p. injection of vehicle, E(2), or E(2) plus P. Consistent with our previous work [Fernandez SM, Lewis MC, Pechenino AS, Harburger LL, Orr PT, Gresack JE, Schafe GE, Frick KM (2008) Estradiol-induced enhancement of object memory consolidation involves hippocampal extracellular signal-regulated kinase activation and membrane-bound estrogen receptors. J Neurosci 28:8660-8667], E(2) alone significantly increased phospho-p42 ERK protein levels in the dorsal hippocampus relative to vehicle controls. In contrast, no combination of E(2) and P affected dorsal hippocampal phospho-ERK levels. These data indicate that, unlike E(2) alone, the beneficial effects of combined E(2) plus P treatment on memory are not associated with ERK activation in the dorsal hippocampus 1 h after treatment, and suggest that E(2) alone and combined E(2) plus P may influence ERK activation in different time frames or enhance memory through different mechanisms.

The extracellular signal-regulated kinase (ERK) pathway is critical for various forms of learning and memory, and is activated by the potent estrogen 17beta-estradiol (E(2)). Here, we asked whether E(2) modulates memory via ERK activation and putative membrane-bound estrogen receptors (ERs). Using ovariectomized mice, we first demonstrate that intraperitoneal injection of 0.2 mg/kg E(2) significantly increases dorsal hippocampal levels of phosphorylated ERK protein 1 h after injection. Second, we show that E(2) administered intraperitoneally (0.2 mg/kg) or via intrahippocampal infusion (5.0 microg/side) immediately after training in an object recognition task significantly enhances memory retention, and that the beneficial effect of intraperitoneal E(2) is blocked by dorsal hippocampal inhibition of ERK activation. Third, using bovine serum albumin-conjugated 17beta-estradiol (BSA-E(2)), we demonstrate that E(2) binding at membrane-bound ERs can increase dorsal hippocampal ERK activation and enhance object memory consolidation in an ERK-dependent manner. Fourth, we show that this effect is independent of nuclear ERs, but is dependent on the dorsal hippocampus. By demonstrating that E(2) enhances memory consolidation via dorsal hippocampal ERK activation, this study is the first to identify a specific molecular pathway by which E(2) modulates memory and to demonstrate a novel role for membrane-bound ERs in mediating E(2)-induced improvements in hippocampal memory consolidation.