Selective depletion of kisspeptin neurons in the hypothalamic arcuate nucleus in early juvenile life reduces pubertal LH secretion and delays puberty onset in mice

• Published in: The FASEB journal 2024-10, Vol.38 (19), p.e70078-n/a
• Main Authors: Coutinho, Eulalia A., Esparza, Lourdes A., Steffen, Paige H., Liaw, Reanna, Bolleddu, Shreyana, Kauffman, Alexander S.
• Format: Article
• Language: English
• Subjects: Animals; Arcuate Nucleus of Hypothalamus - metabolism; Female; GnRH; Gonadotropin-Releasing Hormone - metabolism; hypothalamus; Kiss1; kisspeptin; Kisspeptins - genetics; Kisspeptins - metabolism; LH pulses; LH surge; luteinizing hormone; Luteinizing Hormone - metabolism; Male; Mice; Mice, Transgenic; Neurons - metabolism; puberty; reproduction; sexual maturation; Sexual Maturation - physiology
• ISSN: 0892-6638; 1530-6860; 1530-6860
• DOI: 10.1096/fj.202401696R

Puberty is the critical developmental transition to reproductive capability driven by the activation of gonadotropin‐releasing hormone (GnRH) neurons. The complex neural mechanisms underlying pubertal activation of GnRH secretion still remain unknown, yet likely include kisspeptin neurons. However, kisspeptin neurons reside in several hypothalamic areas and the specific kisspeptin population timing pubertal onset remains undetermined. To investigate this, we strategically capitalized on the differential ontological expression of the Kiss1 gene in different hypothalamic nuclei to selectively ablate just arcuate kisspeptin neurons (aka KNDy neurons) during the early juvenile period, well before puberty, while sparing RP3V kisspeptin neurons. Both male and female transgenic mice with a majority of their KNDy neurons ablated (KNDyABL) by diphtheria toxin treatment in juvenile life demonstrated significantly delayed puberty onset and lower peripubertal LH secretion than controls. In adulthood, KNDyABL mice demonstrated normal in vivo LH pulse frequency with lower basal and peak LH levels, suggesting that only a small subset of KNDy neurons is sufficient for normal GnRH pulse timing but more KNDy cells are needed to secrete normal LH concentrations. Unlike prior KNDy ablation studies in rats, there was no alteration in the occurrence or magnitude of estradiol‐induced LH surges in KNDyABL female mice, indicating that a complete KNDy neuronal population is not essential for normal LH surge generation. This study teases apart the contributions of different kisspeptin neural populations to the control of puberty onset, demonstrating that a majority of KNDy neurons in the arcuate nucleus are necessary for the proper timing of puberty in both sexes. The complex neural mechanisms controlling puberty likely include kisspeptin neurons, but the specific kisspeptin population that times pubertal onset remains undetermined. To test this, we selectively depleted Arcuate nucleus (ARC) kisspeptin neurons while sparing RP3V kisspeptin neurons. Transgenic mice with most ARC kisspeptin neurons ablated by diphtheria toxin (DT) treatment in juvenile life demonstrated delayed puberty onset and reduced peripubertal LH levels. This study demonstrates the important contribution of ARC kisspeptin neurons to the normal timing of puberty in both sexes.