STAT5 signaling in kisspeptin cells regulates the timing of puberty

•Prolactin depolarizes 20% of AVPV kisspeptin neurons in a PI3K-dependent fashion.•TTX co-treatment abolishes prolactin-induced depolarization of AVPV kisspeptin neurons.•The membrane excitability of the ARH kisspeptin neurons is not affected by prolactin.•Kiss1-specific STAT5 ablation accelerates the onset of estrous cyclicity.•Stat5 expression in kisspeptin cells is not required for fertility in adult mice.

Previous studies have shown that kisspeptin neurons are important mediators of prolactin's effects on reproduction. However, the cellular mechanisms recruited by prolactin to affect kisspeptin neurons remain unknown. Using whole-cell patch-clamp recordings of brain slices from kisspeptin reporter mice, we observed that 20% of kisspeptin neurons in the anteroventral periventricular nucleus was indirectly depolarized by prolactin via an unknown population of prolactin responsive neurons. This effect required the phosphatidylinositol 3-kinase signaling pathway. No effects on the activity of arcuate kisspeptin neurons were observed, despite a high percentage (70%) of arcuate neurons expressing prolactin-induced STAT5 phosphorylation. To determine whether STAT5 expression in kisspeptin cells regulates reproduction, mice carrying Stat5a/b inactivation specifically in kisspeptin cells were generated. These mutants exhibited an early onset of estrous cyclicity, indicating that STAT5 transcription factors exert an inhibitory effect on the timing of puberty.