Inducible Kiss1 knockdown in the hypothalamic arcuate nucleus suppressed pulsatile secretion of luteinizing hormone in male mice

Apr 28, 2020The Journal of reproduction and development

Reducing Kiss1 in the hypothalamus lowers hormone pulses controlling reproduction in male mice

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Abstract

Inducible conditional Kiss1 knockdown in male mice resulted in a profound decrease in both the number of Kiss1-expressing cells and luteinizing hormone (LH) pulse frequency at 4 weeks.

Kisspeptin-GPR54 signaling is crucial for the secretion of gonadotropin-releasing hormone (GnRH) and reproductive functions in mammals.
Conventional Kiss1 knockout mice are infertile, but the effects of inducible central Kiss1 knockdown on gonadotropin release had not been previously studied.
After AAV-Cre injection, a significant reduction in ARC Kiss1-expressing cells and LH pulse frequency was observed at 4 weeks.
Despite suppressed ARC Kiss1 expression, pulsatile LH secretion was still detected 8 weeks post-injection.
Control mice showed normal LH pulses and Kiss1 expression in the ARC at both 4 and 8 weeks after AAV-GFP injection.
These findings suggest that ARC kisspeptin neurons contribute to LH secretion and indicate a potential compensatory mechanism for GnRH/LH pulse generation.

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Accumulating evidence suggests that kisspeptin-GPR54 signaling is indispensable for gonadotropin-releasing hormone (GnRH)/gonadotropin secretion and consequent reproductive functions in mammals. Conventional Kiss1 knockout (KO) mice and rats are reported to be infertile. To date, however, no study has investigated the effect of inducible central Kiss1 KO/knockdown on pulsatile gonadotropin release in male mammals. Here we report an in vivo analysis of inducible conditional Kiss1 knockdown male mice. The mice were generated by a bilateral injections of either adeno-associated virus (AAV) vectors driving Cre recombinase (AAV-Cre) or AAV vectors driving GFP (AAV-GFP, control) into the hypothalamic arcuate nucleus (ARC) of Kiss1-floxed male mice, in which exon 3 of the Kiss1 gene were floxed with loxP sites. Four weeks after the AAV-Cre injection, the mice showed a profound decrease in the both number of ARC Kiss1-expressing cells and the luteinizing hormone (LH) pulse frequency. Interestingly, pulsatile LH secretion was apparent 8 weeks after the AAV-Cre injection despite the suppression of ARC Kiss1 expression. The control Kiss1-floxed mice infected with AAV-GFP showed apparent LH pulses and Kiss1 expression in the ARC at both 4 and 8 weeks after the AAV-GFP injection. These results with an inducible conditional Kiss1 knockdown in the ARC of male mice suggest that ARC kisspeptin neurons are responsible for pulsatile LH secretion in male mice, and indicate the possibility of a compensatory mechanism that restores GnRH/LH pulse generation.

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Inducible Kiss1 knockdown in the hypothalamic arcuate nucleus suppressed pulsatile secretion of luteinizing hormone in male mice

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