Activational and Organizational Effects of Sex Hormones on Hippocampal Inhibitory Neurons

Peripheral and brain-produced sex hormones exert sex-specific regulation of hippocampal cognitive function. Estrogens produced by neuronal aromatase regulate inhibitory neurons (INs) and hippocampal-dependent memory in adult female mice, but not in males. How and when this sex effect is established and how peripheral and brain sources of estrogens interact in the control of hippocampal INs is currently unknown. Using ex-vivo electrophysiology, fiber photometry, molecular analysis, estrous cycle monitoring and neonatal hormonal manipulations, we unveil estrous cycle dependent and independent features of CA1 Parvalbumin (PV) INs and hippocampal inhibition in adult female mice. Before puberty, aromatase is expressed in PV INs and regulates synaptic inhibition in female but not in male mice. Neonatal testosterone administration altered prepubertal female mouse hippocampus-dependent memory, PV IN function and estrogenic regulation of adult female synaptic inhibition and PV IN perineuronal nets. Our results suggest that sex differences in brain-derived estrogen regulation of CA1 inhibition are established by organizational effects of neonatal gonadal hormones and highlight the role of INs as mediators of the sexual differentiation of the hippocampus.<b>Significance statement</b> The actions of sex hormones on the hippocampus, a brain region involved in memory, differ between males and females but how and when these differences are established is not known. Our work identifies a population of hippocampal inhibitory neurons (INs) that are sensitive to hormonal fluctuations associated with the female estrous cycle. INs may produce estrogen, the main female sex hormone, before the onset of adult gonadal production (puberty). Brain-produced estrogen regulates female, but not male, juvenile INs, an effect that is abolished by a neonatal surge of testosterone that typically occurs in males around birth. Thus, early in life, sex hormones impact IN function suggesting a role for this neuronal population in the sexual differentiation of the hippocampus.