Sex Differences in the Rapid Cell Signaling Mechanisms Underlying the Memory-Enhancing Effects of 17β-Estradiol

Little is known about how 17β-estradiol (E(2)) mediates memory formation in males. In ovariectomized (OVX) mice, bilateral dorsal hippocampal (DH) infusion of E(2) enhances memory consolidation in object recognition (OR) and object placement (OP) tasks in a manner dependent on activation of extracellular signal-regulated kinase (ERK) and Akt signaling. Here, bilateral DH E(2) infusion enhanced memory consolidation in both tasks among OVX female, gonadally-intact male, and castrated male mice, suggesting comparable facilitation of memory consolidation in both sexes, independent of testicular hormones in males. Contrary to previous reports in OVX mice, E(2) did not increase DH ERK or Akt phosphorylation in males, nor did the ERK inhibitor U0126 [1,4-diamino-2,3-dicyano-1,4-bis (o-aminophenylmercapto) butadiene] prevent E(2) from enhancing memory consolidation among intact and castrated males. These data suggest that ERK activation is not necessary for E(2) to enhance memory consolidation in males, and compared with previous reports in females, reveal novel sex differences in the cell-signaling pathways through which E(2) facilitates memory consolidation. To explore the mechanisms underlying E(2)-induced memory enhancements in males, phosphorylation of the transcription factor cAMP response element binding protein (CREB) in the DH was assessed. E(2) increased phospho-CREB levels in both sexes, yet U0126 did not block these increases in castrated or intact males, indicating that E(2) regulates CREB phosphorylation in males via an ERK-independent mechanism. Collectively, these findings suggest that the beneficial effects of hippocampal E(2) on memory consolidation in males and females are mediated by different molecular mechanisms, which has important implications for the development of treatments to reduce memory dysfunction in men and women.