Faculty Collaboration Database

The mTOR and canonical Wnt signaling pathways mediate the mnemonic effects of progesterone in the dorsal hippocampus. Hippocampus 2015 May;25(5):616-29

Date

12/09/2014

Pubmed ID

25483228

DOI

10.1002/hipo.22398

Scopus ID

2-s2.0-84928371263 (requires institutional sign-in at Scopus site)   24 Citations

Abstract

Although much is known about the neural mechanisms responsible for the mnemonic effects of 17β-estradiol (E2 ), very little is understood about the mechanisms through which progesterone (P4 ) regulates memory. We previously showed that intrahippocampal infusion of P4 in ovariectomized female mice enhances object recognition (OR) memory consolidation in a manner dependent on activation of dorsal hippocampal ERK and mTOR signaling. However, the role of specific progesterone receptors (PRs) in mediating the effects of progesterone on memory consolidation and hippocampal cell signaling are unknown. Therefore, the goals of this study were to investigate the roles of membrane-associated and intracellular PRs in mediating hippocampal memory consolidation, and identify downstream cell signaling pathways activated by PRs. Membrane-associated PRs were targeted using bovine serum albumin-conjugated progesterone (BSA-P), and intracellular PRs (PR-A, PR-B) were targeted using the intracellular PR agonist R5020. Immediately after OR training, ovariectomized mice received bilateral dorsal hippocampal infusion of vehicle, P4 , BSA-P, or R5020. OR memory consolidation was enhanced by P4 , BSA-P, and R5020. However, only P4 and BSA-P activated ERK and mTOR signaling. Furthermore, dorsal hippocampal infusion of the ERK inhibitor U0126 blocked the memory-enhancing effects of BSA-P, but not R5020. The intracellular PR antagonist RU486 blocked the memory-enhancing effects of R5020, but not BSA-P. Interestingly, P4 robustly activated canonical Wnt signaling in the dorsal hippocampus, which is consistent with our recent findings that canonical Wnt signaling is necessary for OR memory consolidation. R5020, but not BSA-P, also elicited a modest increase in canonical Wnt signaling. Collectively, these data suggest that activation of ERK signaling is necessary for membrane-associated PRs to enhance OR, and indicate a role for canonical Wnt signaling in the memory-enhancing effects of intracellular PRs. This study provides the first evidence that membrane and intracellular PRs may employ different molecular mechanisms to enhance hippocampal memory.

Author List

Fortress AM, Heisler JD, Frick KM

Author

Karyn Frick BA,MA,PhD Professor in the Psychology department at University of Wisconsin - Milwaukee

MESH terms used to index this publication - Major topics in bold

Animals
Catheters, Indwelling
Cell Membrane
Female
Hippocampus
Intracellular Space
MAP Kinase Signaling System
Memory Consolidation
Mice, Inbred C57BL
Ovariectomy
Progesterone
Receptors, Progesterone
TOR Serine-Threonine Kinases
Wnt Signaling Pathway