Direct regulation of postnatal GnRH neurons by the progesterone derivativeallopregnanolone in the mouse

The mechanisms through which gonadal steroids exert critical feedback actio ns upon the activity of the GnRH neurons are not understood. We have examin ed here whether progesterone may modulate the electrical activity of the Gn RH neurons following its rapid metabolism to the neuroactive steroid allopr egnanolone within the brain. Using an acute brain slice preparation, whole- cell, patch-clamp recordings were made from GnRH neurons of juvenile (postn atal d 15-20) and adult (postnatal d 60-70) female mice in the presence of tetrodotoxin. Progesterone (1 muM) was not observed to have any actions (up to 5 min exposure) upon GnRH neurons. However, allopregnanolone (500 nM-1 muM) exerted rapid (<1 min) effects upon the baseline membrane potential of all GnRH neurons and also significantly (P < 0.01) enhanced their GABA res ponses by up to 4-fold. All GABA and allopregnanolone responses were abolis hed by the GABA(A) receptor antagonist bicuculline. No differences were det ected in the allopregnanolone sensitivity of GnRH neurons recorded from juv enile and adult GnRH neurons. These results provide the first evidence for a direct action of the neurosteroid allopregnanolone on postnatal GnRH neur ons and suggest a new mechanism through which fluctuating progesterone leve ls may influence the secretory activity of these important neurons in the f emale mouse.