Neuronal plasticity at puberty in mouse hypothalamic Kiss1 neurons that control fertility

Yuanxin, Zhang and Leonie, M. Pakulat and Takács, Szabolcs Ferenc and Lauren, Campbell and Elisa, Galliano and Hrabovszky, Erik and William, H. Colledge and Susan, Jones (2025) Neuronal plasticity at puberty in mouse hypothalamic Kiss1 neurons that control fertility. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 122 (43). No. e2512855122. ISSN 0027-8424

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Abstract

Puberty is a critical transition period to achieve reproductive capacity in all mammalian species. At puberty, hypothalamic Kiss1 neurons release kisspeptin, stimulating gonadotropin-releasing hormone (GnRH) release and activating the hypothalamic– pituitary–gonadal (HPG) axis. Here, we show that Kiss1 neurons in the arcuate nucleus of the hypothalamus (Kiss1ARC) of female mice undergo profound intrinsic plasticity at puberty. Kiss1ARC neurons in brain slices from 3-wk-old mice, when depolarized, typically fire a short high-frequency burst of action potentials before falling silent. This would make them unsuitable for the sustained activity that is required to activate pulsatile GnRH secretion and the HPG axis. At 4 wk of age and after puberty, Kiss1ARC neurons can fire a sustained train of action potentials. There is a concomitant hyperpolarization in action potential threshold and postspike minimum voltage and larger medium after-hyperpolarizations (mAHP) and hyperpolarization-induced voltage sags. Transcriptomic profiling showed significant changes in ion channel expression after puberty. Using quantitative PCR, we confirmed changes in genes encoding voltage-gated sodium, calcium, potassium, and cation channels. Blocking hyperpolarization-induced cation channels caused Kiss1ARC neurons from postpuberty mice to fire less sustained trains of action potentials. Recordings from Kiss1ARC neurons in mice after ovariectomy and 17β-estradiol replacement revealed a critical window of estrogen-dependent plasticity between 3 and 6 wk, which is essential for the maturation of Kiss1ARC neurons and the development of their adult electrophysiological activity. This represents an example of sex steroid–dependent plasticity in the mammalian brain at puberty.

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