Glutamatergic Input From Arcuate Nucleus Kiss1 Neurons to Preoptic Kiss1 Neurons Is Required for LH Surge in Female Mice

Jian Qiu, Rajae Talbi, Martha A Bosch, Elizabeth Medve, Larry S Zweifel, Oline K Rønnekleiv, Víctor M Navarro, Martin J Kelly
Endocrinology, Volume 166, Issue 2, February 2025, bqaf015
https://doi.org/10.1210/endocr/bqaf015

Abstract

Hypothalamic kisspeptin (Kiss1) neurons are vital for maintaining fertility in the mammal. In the female rodent, Kiss1 neurons populate the anteroventral periventricular/periventricular nuclei (Kiss1^AVPV/PeN) and the arcuate nucleus (Kiss1^ARH). Kiss1^ARH neurons (also known as KNDy neurons since they coexpress neurokinin B and dynorphin) are considered the “pulse-generator” neurons that presynaptically excite gonadotropin-releasing hormone (GnRH) axons in the median eminence, whereas the Kiss1^AVPV/PeN neurons are the “surge-generator” neurons that depolarize preoptic GnRH neurons directly to drive ovulation. Traditionally, it is believed that Kiss1^ARH neurons are relatively quiet during the late follicular, preovulatory stage of the reproductive cycle due to the 17β-estradiol (E2)-mediated downregulation of the expression of the KNDy peptides. However, based on our single-cell, quantitative polymerase chain reaction and whole-cell electrophysiological recordings, we found that the messenger RNA (mRNA) expression of vesicular glutamate transporter 2 (Vglut2) mRNA and excitatory cation channels in Kiss1^ARH neurons were significantly upregulated by E2, which increased the excitability and glutamate release from these “pulse-generator” neurons. Presently, we demonstrate that optogenetic stimulation of Kiss1^ARH neurons releases glutamate to excite Kiss1^AVPV/PeN neurons via activation of both ionotropic and metabotropic glutamate receptors. CRISPR mutagenesis of Vglut2 in Kiss1^ARH neurons abolished glutamatergic neurotransmission, which significantly reduced the overall glutamatergic input to Kiss1^AVPV/PeN neurons. The mutagenesis of Vglut2 in Kiss1^ARH neurons abrogated the E2-induced luteinizing hormone surge and reduced the formation of corpus lutea, indicative of a reduced ovulatory drive in these Vglut2-mutated Kiss1^ARH mice. Therefore, Kiss1^ARH neurons appear to play a critical role in augmenting the GnRH surge through glutamatergic neurotransmission to Kiss1^AVPV/PeN neurons.

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