Aromatase inhibition modulates intrinsic properties and excitability of hippocampal CA1 pyramidal cells in the APP/PS1 mouse model of Alzheimer's disease

Changes in the hippocampus stemming from heightened neuronal excitability contribute to memory loss in AD. In this context the role of estradiol, the primary estrogen in the brain, is mixed as it generally supports cognition but is also pro-convulsive. In addition to circulating ovarian estradiol in females, neurons in both males and females, including many of those in the hippocampus, express the enzyme aromatase, which converts testosterone to estradiol. Previous studies suggest that aromatase inhibition modulates hippocampal function and excitability, demonstrating actions of local neuroestradiol. However, how the role of estradiol in regulating hippocampal excitability changes in the context of AD is unknown. Here we investigated whether inhibition of aromatase modifies hippocampal CA1 pyramidal cell intrinsic excitability in the APP/PS1 mouse model of AD, which is prone to hyperexcitability and seizures. Mice at 11-14 weeks old received daily injections of the aromatase inhibitor letrozole or vehicle for 7 days. 24 h after the final injection, acute slices through the dorsal hippocampus were prepared and the response function of CA1 pyramidal cells to injected current was measured using whole-cell patch-clamp electrophysiology. CA1 pyramidal cells in vehicle-treated gonad-intact APP/PS1 mice showed increased excitability compared to those in wild-type counterparts, and this difference was reversed by letrozole. Furthermore, the effects of APP/PS1 genotype and of letrozole in females were abolished after ovariectomy. Overall, these results suggest that estradiol plays a complex role in regulating hippocampal excitability in AD.

APP/PS1; Alzheimer's disease; CA1 pyramidal cells; Cellular excitability; Estradiol; hippocampus.