Neurosteroids alter gamma-aminobutyric acid postsynaptic currents in gonadotropin-releasing hormone neurons: a possible mechanism for direct steroidal control.
Pulsatile GnRH release is required for fertility and is regulated by steroid feedback. Whether or not steroids or their metabolites act directly on GnRH neurons is not well established. In some neurons, steroid metabolites known as neurosteroids modulate the function of the GABAA receptor. Specifically, the progesterone derivative allopregnanolone is an allosteric agonist at this receptor, whereas the androgen dehydroepiandrosterone sulfate (DHEAS) is an allosteric antagonist. We hypothesized these metabolites act similarly on GnRH neurons to modify the response to GABA. Whole-cell voltage-clamp recordings of GABAergic miniature postsynaptic currents (mPSCs) were made from green fluorescent protein-identified GnRH neurons in brain slices from diestrous mice. Glutamatergic currents were blocked with antagonists and action potentials blocked with tetrodotoxin, minimizing presynaptic effects of treatments. Allopregnanolone (5 microm) increased mPSC rate of rise, amplitude and decay time by 15.9 +/- 6.1%, 16.5 +/- 6.3%, and 58.3 +/- 18.6%, respectively (n = 7 cells). DHEAS (5 microm) reduced mPSC rate of rise (32.1 +/- 5.7%) and amplitude (27.6 +/- 4.3%) but did not alter decay time (n = 8). Effects of both neurosteroids were dose dependent between 0.1 and 10 microm. In addition to independent actions, DHEAS also reversed effects of allopregnanolone on rate of rise and amplitude so that these parameters were returned to pretreatment baseline values (n = 6). These data indicate allopregnanolone increases and DHEAS decreases responsiveness of GnRH neurons to activation of GABAA receptors by differentially modulating current flow through GABAA receptor chloride channels. This provides one mechanism for direct steroid feedback to GnRH neurons.
Sullivan
Shannon D
SD
Department of Internal Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.
Moenter
Suzanne M
SM
D000818:Animals; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology*; D004553:Electric Conductivity; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011280:Pregnanolone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011312:Pressure; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology
D007987:Gonadotropin-Releasing Hormone; D005680:gamma-Aminobutyric Acid; D019314:Dehydroepiandrosterone Sulfate; D011280:Pregnanolone