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

Abstract:

The arcuate nucleus kisspeptin (ARNKISS) neurons intermittently synchronize their activity to operate as the GnRH pulse generator and drive pulsatile reproductive hormone secretion in mammals. Although ARNKISS neurons are known to receive various GABAergic inputs, the effects of GABAA and GABAB receptor modulation on their ability to synchronize remain unknown. We have used GCaMP6s to monitor the activity of multiple ARNKISS neurons simultaneously in acute brain slices from diestrous female Kiss1-Cre1,Ai162D mice. The effects of modulating GABAA and GABAB receptors on calcium transients exhibited by individual ARNKISS 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 GABAA receptor agonist muscimol had a biphasic effect in which ARNKISS 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 GABAB receptor agonist, also reduced the frequency of ARNKISS neuron burst firing. The receptor antagonists bicuculline and CGP-35348 had no effects on individual bursting frequency or dynamics, or the synchronous activation of ARNKISS 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 GABAA receptor-mediated depolarization, sustained GABAergic input to ARNKISS neurons suppresses their burst firing and ability to synchronize through both GABAA and GABAB receptors. As such, GABAergic inputs to ARNKISS neurons appear to have considerable potential to modulate the frequency of pulse generator activity in female mice.