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Estradiol Negative Feedback Regulation by Glutamatergic Afferents to A15 Dopaminergic Neurons: Variation with Season

Department of Physiology and Pharmacology (S.R.S., S.M.H., J.M.C., C.J.M., R.L.G.), West Virginia University, Morgantown, West Virginia 26506; and Departments of Anatomy and Cell Biology (M.N.L.) and Physiology and Pharmacology (L.M.C.), University of Western Ontario, London, Ontario, Canada N6A 5C1

Address all correspondence and requests for reprints to: Robert L. Goodman, Department of Physiology and Pharmacology, P.O. Box 9229, West Virginia University, Morgantown, West Virginia 26506-9229. E-mail: bgoodman{at}hsc.wvu.edu.

It is now clear that seasonal breeding in ewes is due to an increase in response to estradiol (E₂) negative feedback in the nonbreeding season (anestrus) that is mediated by the A15 group of dopaminergic (DA) neurons. Because A15 cells do not contain estrogen receptors, we have postulated the presence of estrogen-responsive afferents and recently reported evidence that input from neurons containing -aminobutyric acid (GABA) contribute to the control of A15 activity by E₂. However, GABAergic afferents account for only a fraction of A15 synaptic input and do not appear to vary with season. We therefore investigated the possible role of stimulatory glutamatergic input to A15 neurons. In experiments 1 and 2, local administration into the A15 of either a N-methyl-D-aspartate (NMDA) receptor or a kainate/-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor antagonist stimulated episodic LH secretion in a dose-dependent manner in ovary-intact anestrous ewes. In experiment 3, we examined the number of glutamatergic close contacts onto A15 neurons using dual immunocytochemistry in tissue from E₂-treated ovariectomized anestrous and breeding season ewes. All A15 DA neurons were contacted by glutamatergic vesicles, and the number of close contacts was significantly higher in anestrus than the breeding season. Finally, using a triple-label immunocytochemistry procedure, we did not observe any colocalization of markers for GABA and glutamate in vesicles contacting A15 neurons. These results support the hypothesis that glutamatergic afferents actively stimulate A15 DA neurons in ovary-intact anestrous ewes and raise the possibility that alterations in this input may contribute to increased A15 neural activity during anestrus.