Lack of Pulse and Surge Modes and Glutamatergic Stimulation of Luteinising Hormone Release in Kiss1 Knockout Rats

Abstract

Kisspeptin, encoded by the Kiss1 gene, has attracted attention as a key candidate neuropeptide in controlling puberty and reproduction via regulation of gonadotrophin-releasing hormone (GnRH) secretion in mammals. Pioneer studies with Kiss1 or its cognate receptor Gpr54 knockout (KO) mice showed the indispensable role of kisspeptin-GPR54 signalling in the control of animal reproduction, although detailed analyses of gonadotrophin secretion, especially pulsatile and surge-mode of luteinising hormone (LH) secretion, were limited. Thus, in the present study, we have generated Kiss1 KO rats aiming to evaluate a key role of kisspeptin in governing reproduction via pulse and surge modes of GnRH/LH secretion. Kiss1 KO male and female rats showed a complete suppression of pulsatile LH secretion, which is responsible for folliculogenesis and spermatogenesis, and an absence of puberty and atrophic gonads. Kiss1 KO female rats showed no spontaneous LH/follicle-stimulating hormone surge and an oestrogen-induced LH surge, suggesting that the GnRH surge generation system, which is responsible for ovulation, does not function without kisspeptin. Furthermore, challenge of major stimulatory neurotransmitters, such as monosodium glutamate, NMDA and norepinephrine, failed to stimulate LH secretion in Kiss1 KO rats, albeit they stimulated LH release in wild-type controls. Taken together, the results of the present study confirm that kisspeptin plays an indispensable role in generating two modes (pulse and surge) of GnRH/gonadotrophin secretion to regulate puberty onset and normal reproductive performance. In addition, the present study suggests that kisspeptin neurones play a critical role as a hub integrating major stimulatory neural inputs to GnRH neurones, using newly established Kiss1 KO rats, which serve as a useful model for detailed analysis of hormonal profiles.

Ovarian function and reproductive senescence in the rat: role of ovarian sympathetic innervation

“…Hypothalamic KP is considered a master regulator of the gonadotropic axis and is critical for the onset of puberty in mammals (Pinilla et al 2012). Knockout (KO) mice of the kisspeptin receptor (GPR54 −/− ) (Colledge 2009) and the novel Kiss1 KO rats (Uenoyama et al 2015) do not reach puberty and are infertile due to the absence of gonadotropin secretion. KP and its receptor KISS1R are expressed in the ovary of different species including humans, rats and mice, and their expression and immunolocalisation are in theca cells (TCs) (Castellano et al 2006, Gaytan et al 2009, Zhou et al 2014) and granulosa cells (GCs) (Ricu et al 2012, Laoharatchatathanin et al 2015.…”

Definition of the hypothalamic GnRH pulse generator in mice

“…Humans and rodents with global deletions or mutations in kisspeptin or the kisspeptin receptor fail to exhibit normal pulsatile luteinizing hormone (LH) secretion (9,10,12,13). Of the two kisspeptin neuron populations that innervate GnRH neurons, particular attention has focused upon the arcuate nucleus kisspeptin (ARN KISS ) neurons in terms of pulse generation (14,15).…”

Metabolism and Energy Expenditure, But Not Feeding or Glucose Tolerance, Are Impaired in Young Kiss1r KO Female Mice

“…Humans, mice, and rats with mutations in these genes show impaired puberty, hypogonadism, and infertility (1)(2)(3)(4)(5)(6). In addition to being expressed in reproductive areas of the brain, kisspeptin is also expressed in multiple peripheral tissues (7)(8)(9)(10).…”