The amino acid γ-aminobutyric acid (GABA) is thought to play a key role in shaping the activity of the GnRH neurons throughout embryonic and postnatal life. However, the physiological roles of direct GABA inputs to GnRH neurons remain unknown. Using a Cre-LoxP strategy, we generated a targeted mouse line, in which all (98 ± 1%) GnRH neurons had the γ2-subunit of the GABAA receptor deleted. Electrophysiological recordings of GABAA-mediated postsynaptic currents from green fluorescent protein-tagged GnRH neurons with the γ2-subunit knocked out (GnRH γ2 KO) showed that the amplitude and frequency of GABAA postsynaptic currents were reduced by 70% (P < 0.01) and 77% (P < 0.05), respectively, and that the response to exogenous GABA was reduced by 90% (P < 0.01). Evaluation of male and female GnRH γ2 KO mice revealed completely normal fecundity, estrous cycles, and puberty onset. Further investigation with gonadectomy and different steroid replacement regimens showed normal basal levels of LH in both sexes, and a normal estradiol-evoked positive feedback mechanism in females. However, the increment in LH after gonadectomy in GnRH γ2 KO female mice was double that of controls (P < 0.05) and also more potently suppressed by 17-β-estradiol (P < 0.05). A similar but nonsignificant trend was observed in GnRH γ2 KO male mice. Together, these findings show that 70-90% reductions in the normal levels of GABAA receptor activity at the GnRH neuron appear to impact upon the estrogen negative feedback mechanism but are, nevertheless, compatible with normal fertility in mice.
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