Activational and organizational effects of sex hormones on hippocampal inhibitory neurons

Abstract

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 stablished 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 mice hippocampal dependent memory, PV IN function and estrogenic regulation of adult female synaptic inhibition and PV INs 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. HighlightsO_LIEstrous cycle dependent and independent features of CA1 PV INs and hippocampal inhibition C_LIO_LIAromatase is expressed in male and female PV neurons before puberty. C_LIO_LINeuroestrogens regulate prepubertal CA1 synaptic inhibition in females but not in males. C_LIO_LINeonatal testosterone disrupts neuroestrogen effects on adult female hippocampus. C_LIO_LINeonatal testosterone affects PV INs and hippocampal function before puberty. C_LI