Neuronal plasticity at puberty in mouse hypothalamic <i>Kiss1</i> neurons that control fertility.

Abstract

Puberty is a critical transition period to achieve reproductive capacity in all mammalian species. At puberty, hypothalamic <i>Kiss1</i> neurons release kisspeptin, stimulating gonadotropin-releasing hormone (GnRH) release and activating the hypothalamic-pituitary-gonadal (HPG) axis. Here, we show that <i>Kiss1</i> neurons in the arcuate nucleus of the hypothalamus (<i>Kiss1^ARC</i>) of female mice undergo profound intrinsic plasticity at puberty. <i>Kiss1^ARC</i> 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, <i>Kiss1^ARC</i> 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 <i>Kiss1^ARC</i> neurons from postpuberty mice to fire less sustained trains of action potentials. Recordings from <i>Kiss1^ARC</i> 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 <i>Kiss1^ARC</i> neurons and the development of their adult electrophysiological activity. This represents an example of sex steroid-dependent plasticity in the mammalian brain at puberty.