Effect of GABA on GnRH neurons switches from depolarization to hyperpolarization at puberty in the female mouse

The amino acid gamma-aminobutyric acid (GABA) plays an important role in the regulation of the GnRH neurons. We examined whether GABA depolarizes or hyperpolarizes GnRH neurons over postnatal development using gramicidin, perforated-patch electrophysiology combined with GnRH-LacZ transgenic mice in whom GnRH neurons can be made to fluoresce. The basic membrane properties and GABA responsiveness of GnRH neurons were not altered by transgene expression or fluorescence. Ten of 12 immature GnRH neurons (10-17 d) were depolarized by GABA in a direct and dose-dependent manner that was blocked by a GABA(A) receptor antagonist. In peripubertal GnRH neurons (25-30 d), GABA exerted depolarizing (4/11) as well as hyperpolarizing (5/11) effects on GnRH neurons. In adult female mice, GABA was found to exert exclusively hyperpolarizing actions on GnRH neurons (9/10) that were direct and mediated by the GABA(A) receptor. GABA switched from depolarizing to hyperpolarizing actions around postnatal d 31, the time of vaginal opening. Unidentified preoptic area neurons exhibited predominantly hyperpolarizing responses to GABA at all three postnatal stages. These findings demonstrate that GnRH neurons display an unusually late postnatal switch in their response to GABA. They also provide the first direct evidence that GABA inhibits the electrical activity of postpubertal GnRH neurons.