Activation of Gonadotropin-Releasing Hormone Neurons by Kisspeptin as a Neuroendocrine Switch for the Onset of Puberty

Abstract

We examined the role of kisspeptin and its receptor, the G-protein-coupled receptor GPR54, in governing the onset of puberty in the mouse. In the adult male and female mouse, kisspeptin (10 -100 nM) evoked a remarkably potent, long-lasting depolarization of Ͼ90% of gonadotropin-releasing hormone (GnRH)-green fluorescent protein neurons in situ. In contrast, in juvenile [postnatal day 8 (P8) to P19] and prepubertal (P26 -P33) male mice, kisspeptin activated only 27 and 44% of GnRH neurons, respectively. This developmental recruitment of GnRH neurons into a kisspeptin-responsive pool was paralleled by an increase in the ability of centrally administered kisspeptin to evoke luteinizing hormone secretion in vivo. To learn more about the mechanisms through which kisspeptin-GPR54 signaling at the GnRH neuron may change over postnatal development, we performed quantitative in situ hybridization for kisspeptin and GPR54 transcripts. Approximately 90% of GnRH neurons were found to express GPR54 mRNA in both juvenile and adult mice, without a detectable difference in the mRNA content between the age groups. In contrast, the expression of KiSS-1 mRNA increased dramatically across the transition from juvenile to adult life in the anteroventral periventricular nucleus (AVPV; p Ͻ 0.001). These results demonstrate that kisspeptin exerts a potent depolarizing effect on the excitability of almost all adult GnRH neurons and that the responsiveness of GnRH neurons to kisspeptin increases over postnatal development. Together, these observations suggest that activation of GnRH neurons by kisspeptin at puberty reflects a dual process involving an increase in kisspeptin input from the AVPV and a post-transcriptional change in GPR54 signaling within the GnRH neuron.

Suppression of kisspeptin expression and gonadotropic axis sensitivity following exposure to inhibitory day lengths in female Siberian hamsters

“…Additionally, the GnRH receptor antagonist, acyline, blocks gonadotropin release elicited by kisspeptin (Gottsch et al, 2004;Irwig et al, 2004;Shahab et al, 2005). A large proportion of GnRH cells co-express GPR54 mRNA, further supporting a direct mode of action by kisspeptin on GnRH neurons (Han et al, 2005;Irwig et al, 2004;Messager et al, 2005).…”

Membrane-initiated estrogen signaling in hypothalamic neurons

“…However, both negative and positive (induction of the LH surge) feedback regulation of LH (GnRH) secretion can be restored by replacement with E2. The positive feedback is believed to be by an action of E2 in the anteroventral periventricular (AVPV) nucleus (Herbison, 1998, Han et al, 2005, Smith et al, 2006, Wintermantel et al, 2006. Neurons in the AVPV express kisspeptin, a neuropeptide encoded by the Kiss gene, GABA and opioid peptides, all of which are important for regulation of GnRH neurosecretion (Simerly et al, 1988, Wagner et al, 2001a, Jackson and Kuehl, 2002, DeFazio et al, 2002, Smith et al, 2006, Christian and Moenter, 2007.…”

“…The latter findings combined with recent technological advances, such as the development of ER mutants and transgenic animals expressing green fluorescent protein (GFP) in GnRH neurons, have greatly facilitated studies to understand the cellular mechanisms by which GnRH neurons are regulated by estrogen (Spergel et al, 1999, Suter et al, 2000, Kato et al, 2003, Han et al, 2005, Abraham et al, 2003, Smith et al, 2006, Wintermantel et al, 2006. A series of recent publications show that in mouse hypothalamic neuronal explants and in primate nasal placode cultures, E2 augments synchronous intracellular Ca 2+ oscillations in GnRH neurons (Temple et al, 2004, Temple and Wray, 2005, Abe et al, 2007.…”

Caloric restriction: Impact upon pituitary function and reproduction

“…Interestingly, these Kiss neurons are thought to be the primary manner in which hypothalamic neuronal inputs are relayed to the GnRH neurons, which do not appear to express many of the necessary receptors that are required for the induction of the appropriate responses to hormones and factors such as leptin, ghrelin, dopamine, estradiol, and other factors that are related to the nutritional status of the organism (Dungan et al, 2006;Maeda et al, 2007). The activation of Kiss1 gene expression is likely to play an important role in timing the onset of puberty, sexual differentiation of the GnRH/LH surge mechanism, and the preovulatory GnRH/LH surge itself (in females) (Gottsch et al, 2004a;Shahab et al, 2005;Han et al, 2005, Navarro et al, 2004.…”