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The Journal of Neuroscience, August 27, 2008, 28(35):8660-8667; doi:10.1523/JNEUROSCI.1968-08.2008

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

Stephanie M. Fernandez,^1 * Michael C. Lewis,^1 * Angela S. Pechenino,¹ Lauren L. Harburger,¹ Patrick T. Orr,¹ Jodi E. Gresack,¹ Glenn E. Schafe,^1,2 and Karyn M. Frick^1,2

¹Department of Psychology and ²Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut 06520

Correspondence should be addressed to Dr. Karyn M. Frick, Department of Psychology, Yale University, P.O. Box 208205, New Haven, CT 06520. Email: karyn.frick{at}yale.edu

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 E₂ 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 E₂ significantly increases dorsal hippocampal levels of phosphorylated ERK protein 1 h after injection. Second, we show that E₂ administered 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 E₂ is blocked by dorsal hippocampal inhibition of ERK activation. Third, using bovine serum albumin-conjugated 17β-estradiol (BSA-E₂), we demonstrate that E₂ 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 E₂ enhances memory consolidation via dorsal hippocampal ERK activation, this study is the first to identify a specific molecular pathway by which E₂ modulates memory and to demonstrate a novel role for membrane-bound ERs in mediating E₂-induced improvements in hippocampal memory consolidation.

Key words: estrogen; memory; ERK; MAPK; hippocampus; receptor

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Received April 25, 2007; revised June 25, 2007; accepted July 16, 2008.

Correspondence should be addressed to Dr. Karyn M. Frick, Department of Psychology, Yale University, P.O. Box 208205, New Haven, CT 06520. Email: karyn.frick{at}yale.edu

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