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 17␤-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 g/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 17␤-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.

The epigenetics of estrogen

“…53,54 In vivo, we have found that infusions of E 2 directly into the dorsal hippocampus increase dorsal hippocampal p42-ERK phosphorylation within 5 min of infusion. 6,55 Further, we demonstrated that ERK activation is necessary for E 2 to enhance memory formation. 6,55,56 In this series of studies, memory was tested in ovariectomized female mice trained to recognize objects in a novel object recognition task (Fig.…”

“…6,55 Further, we demonstrated that ERK activation is necessary for E 2 to enhance memory formation. 6,55,56 In this series of studies, memory was tested in ovariectomized female mice trained to recognize objects in a novel object recognition task (Fig. 1A) that tests the ability of an animal to recognize an object they have seen before.…”

17β-Estradiol is necessary for extinction of cocaine seeking in female rats

“…Importantly, there is a synergistic overlap between the effects of E 2 and synaptic plasticity associated with extinction learning. For example, E 2 increases activation of mitogen-activated protein kinase (MAPK) cascades during memory consolidation (Fernandez et al 2008), and MAPK signaling is required for extinction (Hugues et al 2004). Thus, E 2 may promote extinction through stimulation of MAPK cascades.…”

Epigenetic alterations regulate estradiol-induced enhancement of memory consolidation

“…We recently showed that activation of the extracellular signal-regulated kinase/ mitogen-activated protein kinase (ERK/MAPK) signaling cascade in the dorsal hippocampus is necessary for the potent estrogen 17β-estradiol (E 2 ) to enhance novel object recognition in young female mice (1). In this study, i.p.…”

“…In this study, i.p. injection of E 2 immediately after object recognition training significantly enhanced long-term memory and increased p42 ERK phosphorylation in the dorsal hippocampus; both effects were blocked by inhibiting MAPK kinase (MEK), the exclusive upstream activator of ERK (1).…”