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Nonclassical Estrogen Modulation of Presynaptic GABA Terminals Modulates Calcium Dynamics in Gonadotropin-Releasing Hormone Neurons

Centre for Neuroendocrinology and Department of Physiology, University of Otago School of Medical Sciences, Dunedin 9054, New Zealand

Address all correspondence and requests for reprints to: Allan E. Herbison, Centre for Neuroendocrinology, Department of Physiology, University of Otago School of Medical Sciences, P.O. Box 913, Dunedin, New Zealand. E-mail: allan.herbison{at}stonebow.otago.ac.nz.

There is increasing recognition that estrogen exerts multifaceted regulatory effects on GnRH neurons. The acute effects of estrogen on calcium dynamics in these cells were examined using a transgenic mouse line that allows real-time measurement of intracellular calcium concentration ([Ca²⁺]i) in GnRH neurons in the acute brain slice preparation. 17-β-Estradiol (E2) at 100 pM–100 nM was found to activate [Ca²⁺]i transients in approximately 40% of GnRH neurons with an approximate 15-min latency. This effect was not replicated by E2-BSA, which limits E2 action to the membrane, 17--estradiol, the inactive isomer at classical estrogen receptors (ERs), or G-1 the GPR30 agonist. E2 continued to activate [Ca²⁺]i transients when transcription was blocked. An ER -selective agonist was equally potent in activating [Ca²⁺]i transients, and E2 remained effective in ERβ knockout x GnRH-Pericam mice. E2’s activation of [Ca²⁺]i transients continued in the presence of tetrodotoxin, which blocks action potential-dependent transmission, but was abolished completely by the further addition of a -aminobutyric acid (GABA)_A receptor antagonist. Exogenous GABA was found to initiate [Ca²⁺]i transients in GnRH neurons. Whole cell, voltage-clamp recordings of GnRH-green fluorescence protein neurons revealed that E2 generated discrete bursts of miniature inhibitory postsynaptic currents with a latency of approximately 15 min. These observations provide evidence for a new mechanism of nonclassical estrogen action within the brain. Estrogen interacts with the classical ER at the level of the GABAergic nerve terminal to regulate action potential-independent GABA release that, in turn, controls postsynaptic calcium dynamics.

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