Estradiol-Induced Enhancement of Object Memory Consolidation Involves Hippocampal Extracellular Signal-Regulated Kinase Activation and Membrane-Bound Estrogen Receptors

Abstract

The extracellular signal-regulated kinase (ERK) pathway is critical for various forms of learning and memory, and is activated by the potent estrogen 17β-estradiol (E₂). Here, we asked whether E₂modulates 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 E₂significantly increases dorsal hippocampal levels of phosphorylated ERK protein 1 h after injection. Second, we show that E₂administered intraperitoneally (0.2 mg/kg) or via intrahippocampal infusion (5.0 μg/side) immediately after training in an object recognition task significantly enhances memory retention, and that the beneficial effect of intraperitoneal E₂is blocked by dorsal hippocampal inhibition of ERK activation. Third, using bovine serum albumin-conjugated 17β-estradiol (BSA-E₂), we demonstrate that E₂binding 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 E₂enhances memory consolidation via dorsal hippocampal ERK activation, this study is the first to identify a specific molecular pathway by which E₂modulates memory and to demonstrate a novel role for membrane-bound ERs in mediating E₂-induced improvements in hippocampal memory consolidation.