Cellular NeuroscienceResting intracellular calcium concentration, depolarizing Gamma-Aminobutyric Acid and possible role of local estradiol synthesis in the developing male and female hippocampus

The maturation of the hippocampus is impacted by a multitude of factors, including the regulation of intracellular calcium levels. Depolarizing actions of Gamma-Aminobutyric Acid (GABA) can profoundly alter intracellular calcium in immature hippocampal neurons via influx through voltage-gated calcium channels. We here report fundamental sex differences in properties of depolarizing GABA responses and in resting intracellular calcium in neonatal cultured hippocampal neurons. The effects of the estrogen receptor antagonist, ICI 182,780, and the estradiol-synthesis inhibitor, formestane, indicate the sex differences in depolarizing GABA responses are at least in part due to de novo estradiol synthesis by female neurons, whereas a sex difference in resting calcium is independent of steroids. We postulate that local estradiol synthesis in cultured female hippocampal neurons affects the kinetics of either the GABAA receptor or voltage sensitive calcium channels. These data highlight the fact that immature hippocampal neurons exhibit fundamentally different physiological properties in males versus females. Elucidating how and where immature male and female neurons differ is essential for a complete understanding of normal rodent brain development.