Estrogenic regulation of hippocampal inhibitory system across lifespan

Estrogens produced in peripheral tissues and locally in the brain are potent neuromodulators. The function of the hippocampus, a brain region essential for episodic memory and spatial navigation, relies on the activity of ensembles of excitatory neurons whose activity is temporally and spatially coordinated by a wide diversity of inhibitory neurons (INs) types. Over the last years, we have accumulated evidence that indicates that estrogens regulate the function of hippocampal INs through different mechanisms, including transcriptional regulation and rapid nongenomic signaling. Here, we argue that the well-documented influence of estrogens on episodic memory may be related to the actions of local and peripheral estrogens on the heterogenous populations of hippocampal INs. We discuss how physiological changes in peripheral sex hormone levels throughout lifespan may interact with local brain sources to regulate IN function at different stages of life, from early hippocampal development to the aging brain. We conclude that considering INs as mediators of sex hormone actions in the hippocampus across the healthy life span will benefit our understanding of sex-biased neurodevelopmental disorders and physiological aging.