title: GABAergic transmission to gonadotropin-releasing hormone (GnRH) neurons is regulated by GnRH in a concentration-dependent manner engaging multiple signaling pathways.
abstract: Gonadotropin-releasing hormone (GnRH) neurons are the central regulators of fertility. GnRH stimulates or inhibits GnRH neuronal activity depending on dose. The mechanisms for these actions remain unknown. We hypothesized GnRH acts in part by altering fast synaptic transmission to GnRH neurons. GABAergic and glutamatergic postsynaptic currents (PSCs), both of which can excite these neurons, were recorded from GnRH neurons in brain slices from adult intact and orchidectomized (ORX) males. ORX enhanced the frequency of GABA transmission to GnRH neurons, but had no effect on glutamatergic transmission. Effects of ORX on GABAergic transmission were reversed by estradiol replacement, suggesting GABA is a mediator of steroid feedback in males. GABAergic neurons express type-1 GnRH receptor (GnRHR-1). Low GnRH (20 nm) reduced GABAergic PSC frequency in GnRH neurons from both ORX and intact mice. High GnRH (2 microm) had no effect on either GABAergic or glutamatergic transmission to GnRH neurons. To investigate mechanisms mediating low-dose GnRH suppression of GABAergic transmission, GABAergic PSCs were recorded after arresting G(alphai) activity with pertussis toxin (PTX). PTX abolished the suppressive effect of low GnRH. Moreover, PTX uncovered a stimulatory effect of high GnRH on GABAergic transmission. These data suggest low-dose GnRH suppresses GnRH firing rate in part by decreasing GABAergic transmission to the GnRH neurons, independent of gonadal hormone milieu. Low-dose GnRH appears to exert the suppressive effect by activating GnRHR-I coupled to G(alphai). The concentration-dependent effects of GnRH may be mediated in part by changes in affinity of GnRH to GnRHR-I coupled to different G(alpha) proteins.
authors: Department of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.
authors: Peilin
authors: P
authors: Chen
authors: Suzanne M
authors: SM
authors: Moenter
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology; D009919:Orchiectomy; D037342:Pertussis Toxin / Q000494:pharmacology; D011966:Receptors, LHRH / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D004967:Estrogens; D009498:Neurotoxins; D011966:Receptors, LHRH; D049452:Green Fluorescent Proteins; D007987:Gonadotropin-Releasing Hormone; D018698:Glutamic Acid; D004958:Estradiol; D005680:gamma-Aminobutyric Acid; D037342:Pertussis Toxin; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1