Activational and organizational effects of sex hormones on hippocampal inhibition
Peripheral and brain-produced sex hormones exert sex-specific regulation of hippocampal cognitive function. Estrogen produced by neuronal aromatase regulates inhibitory neurons (INs) and hippocampal-dependent memory in adult females but not in male mice. How and when this sex effect is stablished and how peripheral and brain sources of estrogen interact in the control of hippocampal INs is currently unknown. Using ex-vivo electrophysiology, molecular analysis, estrous cycle monitoring and neonatal hormonal manipulations, we show evidences that suggest that neuron-derived estrogen and peripheral hormones independently exert activational effects on CA1 synaptic inhibition and perineuronal nets (PNNs) surrounding parvalbumin (PV)-expressing INs. Before puberty, aromatase is expressed in PV INs and regulates synaptic inhibition in female but not in male mice. Neonatal testosterone abolished the effect of brain-derived estrogen on adult female synaptic inhibition and disrupted brain-derived estrogen regulation of PV IN PNNs. Our results suggest that sex differences in brain-derived estrogen effects on 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.