Estradiol-induced object recognition memory consolidation is dependent on activation of mTOR signaling in the dorsal hippocampus

Ashley M. Fortress; Lu Fan; Patrick T. Orr; Zaorui Zhao; Karyn M. Frick

doi:10.1101/lm.026732.112

Estradiol-induced object recognition memory consolidation is dependent on activation of mTOR signaling in the dorsal hippocampus

¹Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, USA
²Department of Psychology, Yale University, New Haven, Connecticut 06520, USA

↵⁸These authors contributed equally to this work.

↵Present addresses: ³Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA; ⁴Department of Neurology, Changhai Hospital, Shanghai 200433, China; ⁵Geisinger Health System, Danville, Pennsylvania 17822, USA; ⁶Department of Anesthesiology and ⁷Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland 21201, USA

Abstract

The mammalian target of rapamycin (mTOR) signaling pathway is an important regulator of protein synthesis and is essential for various forms of hippocampal memory. Here, we asked whether the enhancement of object recognition memory consolidation produced by dorsal hippocampal infusion of 17β-estradiol (E₂) is dependent on mTOR signaling in the dorsal hippocampus, and whether E₂-induced mTOR signaling is dependent on dorsal hippocampal phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) activation. We first demonstrated that the enhancement of object recognition induced by E₂ was blocked by dorsal hippocampal inhibition of ERK, PI3K, or mTOR activation. We then showed that an increase in dorsal hippocampal ERK phosphorylation 5 min after intracerebroventricular (ICV) E₂ infusion was also blocked by dorsal hippocampal infusion of the three cell signaling inhibitors. Next, we found that ICV infusion of E₂ increased phosphorylation of the downstream mTOR targets S6K (Thr-421) and 4E-BP1 in the dorsal hippocampus 5 min after infusion, and that this phosphorylation was blocked by dorsal hippocampal infusion of inhibitors of ERK, PI3K, and mTOR. Collectively, these data demonstrate for the first time that activation of the dorsal hippocampal mTOR signaling pathway is necessary for E₂ to enhance object recognition memory consolidation and that E₂-induced mTOR activation is dependent on upstream activation of ERK and PI3K signaling.