Kisspeptin activates gonadotropin-releasing hormone (GnRH) neurons in mice, playing a critical role in the onset of puberty. The study shows that kisspeptin, a neuropeptide encoded by the KiSS-1 gene, binds to the G-protein-coupled receptor GPR54 and exerts a potent depolarizing effect on GnRH neurons. In adult mice, kisspeptin activates over 90% of GnRH neurons, whereas in juvenile and prepubertal mice, this percentage is significantly lower. The responsiveness of GnRH neurons to kisspeptin increases with postnatal development, suggesting a developmental regulation of this signaling pathway. The expression of KiSS-1 mRNA in the anteroventral periventricular nucleus (AVPV) increases dramatically during the transition from juvenile to adult life, indicating that the AVPV is a key source of kisspeptin input to GnRH neurons. The study also demonstrates that kisspeptin stimulates luteinizing hormone (LH) secretion in vivo, with the effect being more pronounced in adults. The expression of GPR54 mRNA in GnRH neurons is similar in juvenile and adult mice, suggesting that the increased responsiveness to kisspeptin is due to post-transcriptional changes in GPR54 signaling within the GnRH neuron. These findings suggest that the activation of GnRH neurons by kisspeptin during puberty involves both an increase in kisspeptin input from the AVPV and a post-transcriptional change in GPR54 signaling within the GnRH neuron. The study highlights the importance of kisspeptin-GPR54 signaling in the initiation of puberty and suggests that this signaling pathway may serve as a "gatekeeper" for the onset of puberty.Kisspeptin activates gonadotropin-releasing hormone (GnRH) neurons in mice, playing a critical role in the onset of puberty. The study shows that kisspeptin, a neuropeptide encoded by the KiSS-1 gene, binds to the G-protein-coupled receptor GPR54 and exerts a potent depolarizing effect on GnRH neurons. In adult mice, kisspeptin activates over 90% of GnRH neurons, whereas in juvenile and prepubertal mice, this percentage is significantly lower. The responsiveness of GnRH neurons to kisspeptin increases with postnatal development, suggesting a developmental regulation of this signaling pathway. The expression of KiSS-1 mRNA in the anteroventral periventricular nucleus (AVPV) increases dramatically during the transition from juvenile to adult life, indicating that the AVPV is a key source of kisspeptin input to GnRH neurons. The study also demonstrates that kisspeptin stimulates luteinizing hormone (LH) secretion in vivo, with the effect being more pronounced in adults. The expression of GPR54 mRNA in GnRH neurons is similar in juvenile and adult mice, suggesting that the increased responsiveness to kisspeptin is due to post-transcriptional changes in GPR54 signaling within the GnRH neuron. These findings suggest that the activation of GnRH neurons by kisspeptin during puberty involves both an increase in kisspeptin input from the AVPV and a post-transcriptional change in GPR54 signaling within the GnRH neuron. The study highlights the importance of kisspeptin-GPR54 signaling in the initiation of puberty and suggests that this signaling pathway may serve as a "gatekeeper" for the onset of puberty.