Activation of androgen receptors protects intact male mice from memory impairments caused by aromatase inhibition.

Although 17β-estradiol (E2) is known to regulate hippocampal function, the specific contributions of hippocampally-synthesized E2 remain unclear. Infusion of the aromatase inhibitor letrozole into the dorsal hippocampus (DH) of ovariectomized mice disrupts object recognition and object placement memory consolidation, suggesting that DH-synthesized E2 is essential for memory. However, the role of DH-synthesized E2 in memory among male rodents is unknown. Here, we examined effects of aromatase inhibition on memory consolidation in male mice. Intact and gonadectomized mice were infused with vehicle or letrozole into the DH immediately post-training in object placement and object recognition tasks. Letrozole blocked memory in both tasks among gonadectomized males only, suggesting that circulating androgens, or a rise in hippocampal androgens due to aromatase inhibition, may support memory consolidation in intact males. To test this hypothesis, intact males were infused with the androgen receptor antagonist flutamide into the DH after object training. A dose-dependent impairment was observed in both tasks, indicating that blocking androgen signaling can impair memory consolidation. To test if hippocampal androgen receptor activation protected intact males from the impairing effects of letrozole, a non-impairing dose of flutamide was co-infused with letrozole. Co-administration of both drugs blocked object placement and object recognition memory consolidation, demonstrating that letrozole impairs memory in intact males only if androgen receptors are blocked. Together, these data suggest that DH-synthesized E2 and androgen receptor activation may work in concert to mediate memory consolidation in intact males, such that androgen receptor activation protects against memory impairments caused by aromatase inhibition.