SAT-423 The Involvement of GnRH Neurons in Mediating the Effects of RFRP-3 on the Mouse Reproductive Axis

In 2000, gonadotrophin-inhibitory hormone was discovered in birds and shown to inhibit gonadotrophin secretion. The mammalian ortholog was concurrently discovered in humans and rats and termed RFamide-related peptide-3 (RFRP-3). Recent results have shown that the effects of centrally-administered RFRP-3 on gonadotrophin secretion are sex- and cycle stage-dependent in mice (Ancel et al., 2017). Indeed, intracerebroventricular injections of RFRP-3 stimulated LH secretion in males, and inhibited LH secretion in females at the time of the preovulatory LH surge. In addition, the stimulatory effect observed in males was shown to be mediated in part by GPR54, the receptor for Kisspeptins, suggesting the involvement of other pathways. In order to further our understanding of the ways in which RFRP neurons modulate the reproductive axis, we have developed a novel transgenic mouse line. Using a Cre-loxP conditional transgenic method, we knocked the receptor for RFRP-3 (GPR147) out of GnRH neurons and analysed puberty onset in these mice. While the absence of GPR147 on GnRH neurons advanced puberty onset in male mice, it resulted in a delay in female puberty, once again indicating a sex-specific role of the RFRP system in the regulation of the reproductive function. Current work is aimed at dissecting the potential involvement of GnRH neurons in the pathways mediating RFRP-3 effects on LH secretion in mice carrying a deletion of GPR147 in GnRH neurons. Both male and female mice received intracerebroventricular injections of RFRP-3 and LH levels were subsequently assayed in tail-tip blood samples. This work is still ongoing. Taken together, these new tools provide us with the possibility to advance our understanding of the structure and the functions of the RFRP neuronal system in mice.