GABA receptor modulation of arcuate kisspeptin neuron bursting and synchronization activity in female mice

The arcuate nucleus kisspeptin (ARN^KISS) neurons intermittently synchronize their activity to operate as the GnRH pulse generator and drive pulsatile reproductive hormone secretion in mammals. Although ARN^KISS neurons are known to receive various GABAergic inputs, the effects of GABA_A and GABA_B receptor modulation on their ability to synchronize remain unknown. We have used GCaMP6s to monitor the activity of multiple ARN^KISS neurons simultaneously in acute brain slices from diestrous female Kiss1-Cre1,Ai162D mice. The effects of modulating GABA_A and GABA_B receptors on calcium transients exhibited by individual ARN^KISS neurons, reflecting burst firing, and their ability to generate synchronous bursting events were examined. The application of GABA was found to robustly suppress the occurrence of individual calcium transients and population bursting. The GABA_A receptor agonist muscimol had a biphasic effect in which ARN^KISS neurons could initially respond with an increase in baseline calcium but then became inhibited with significantly reduced episodes of individual burst firing and population synchronization events. Baclofen, the GABA_B receptor agonist, also reduced the frequency of ARN^KISS neuron burst firing. The receptor antagonists bicuculline and CGP-35348 had no effects on individual bursting frequency or dynamics, or the synchronous activation of ARN^KISS neurons indicating a lack of ongoing GABA transmission in the acute brain slice. These observations show that while GABAergic activation may initially facilitate excitability through GABA_A receptor-mediated depolarization, sustained GABAergic input to ARN^KISS neurons suppresses their burst firing and ability to synchronize through both GABA_A and GABA_B receptors. As such, GABAergic inputs to ARN^KISS neurons appear to have considerable potential to modulate the frequency of pulse generator activity in female mice.