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Estradiol Enhances Excitatory Gammabutyric Acid-Mediated Calcium Signaling in Neonatal Hypothalamic Neurons¹

Department of Physiology (T.S.P.-S., K.A.G., J.P.Y.K., M.M.M.), University of Maryland School of Medicine, Baltimore, Maryland 21201; Department of Biomedical Sciences (A.M.D.), E. K. Shriver Center, Waltham, Massachusetts 02452; Department of Obstetrics and Gynecology (K.A.G.), University of Maryland School of Medicine, Baltimore, Maryland 21201; and Medical Biotechnology Center (J.P.Y.K.), University of Maryland Biotechnology Institute, Baltimore, Maryland 21201

Address all correspondence and requests for reprints to: Tara Perrot-Sinal, Ph.D., Department of Physiology, BRB 5-020, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, Maryland 21201. E-mail: tperr001{at}umaryland.edu

Contrary to the situation in adulthood, gammabutyric acid (GABA)_A receptor activation during early brain development depolarizes neurons sufficiently to open L-type voltage-gated Ca²⁺ channels. Because GABA is excitatory during the sensitive period of steroid-mediated brain sexual differentiation, we investigated whether estradiol modulates excitatory GABA during this period, by examining two parameters: 1) magnitude of GABA-induced calcium transients; and 2) developmental duration of excitatory GABA. Dissociated hypothalamic neurons from embryonic-day-15 rat embryos were loaded with the Ca²⁺ indicator, fura-2, and transient rises in [Ca²⁺]_i (Ca²⁺ transient) were measured after application of 10 µM muscimol, a GABA_A receptor agonist. Cells were treated with 10^-10 M estradiol or vehicle from 0–3 days in vitro (DIV) and imaged on 4 DIV, whereas others were treated from 3–6 DIV and imaged on 7 DIV. The mean amplitude of Ca²⁺ transients after muscimol administration were 68% and 61% higher in estradiol-treated neurons on 4 DIV and 7 DIV, respectively, relative to controls. Consistent with GABA becoming inhibitory in mature neurons, 50% fewer control neurons responded on DIV 7, relative to DIV 4. However, estradiol treatment maintained excitatory GABA on DIV 7 (72% in estradiol-treated vs. 35% in control). This is the first report of hormonal modulation of excitatory GABA, and it suggests that estradiol may mediate sexual differentiation by enhancing GABA-induced increases in intracellular Ca²⁺.

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