Direct evidence that KNDy neurons maintain gonadotropin pulses and folliculogenesis as the GnRH pulse generator

Abstract

The gonadotropin-releasing hormone (GnRH) pulse is fundamental for mammalian reproduction: GnRH pulse regimens are needed as therapies for infertile women as continuous GnRH treatment paradoxically inhibits gonadotropin release. Circumstantial evidence suggests that the hypothalamic arcuate KNDy neurons expressing <u>k</u>isspeptin (encoded by <i>Kiss1</i>), <u>n</u>eurokinin B (encoded by <i>Tac3</i>), and <u>d</u><u>y</u>norphin A serve as a GnRH pulse generator; however, no direct evidence is currently available. Here, we show that rescuing >20% KNDy neurons by transfecting <i>Kiss1</i> inside arcuate <i>Tac3</i> neurons, but not outside of these neurons, recovered folliculogenesis and luteinizing hormone (LH) pulses, an indicator of GnRH pulses, in female global <i>Kiss1</i> knockout (KO) rats and that >90% conditional arcuate <i>Kiss1</i> KO in newly generated <i>Kiss1</i>-floxed rats completely suppressed LH pulses. These results first provide direct evidence that KNDy neurons are the GnRH pulse generator, and at least 20% of KNDy neurons are sufficient to maintain folliculogenesis via generating GnRH/gonadotropin pulses.