Molecular Biology of the Kisspeptin Receptor: Signaling, Function, and Mutations - Kisspeptin Signaling in Reproductive Biology - page 131

signaling and their implications for the control of GnRH secretion, as well as the
mechanisms by which genetic mutations in this receptor or its ligand kisspeptin
may affect these processes, thereby leading to adverse reproductive outcomes.
Kisspeptin Signaling and Onset of Puberty
KISS1R is Expressed in GnRH Neurons
Expression of Kiss1r in hypothalamic GnRH neurons has been reported in cichlid
fi sh [ 28 ], rats [ 29 ], mice [ 30 ], and Rhesus monkeys [ 31 ]. Activation of Kiss1r by
kisspeptin evokes a powerful and enduring depolarization in more than 90% of
GnRH neurons in adult male and female mice [ 32 ]. Although the precise mecha-
nisms by which Kiss1r signaling leads to this potent depolarization of GnRH neu-
ron are not clear, this effect is likely associated with the distinctive pulsatile release
of GnRH. A signifi cant increase in kisspeptin secretion has been shown in associa-
tion with the pubertal increase in GnRH release in female Rhesus monkeys [ 33 ].
Additionally, GnRH pulses were shown to correlate with kisspeptin pulses in the
stalk-median eminence of these females [ 33 ].
In mice, essentially all Kiss1r-expressing cells in the rostral preoptic area of the
hypothalamus are GnRH neurons [ 34 ]. Interestingly, the percentage of GnRH neu-
rons expressing Kiss1r is sharply reduced after birth, before progressively increas-
ing to 70% by postnatal day 20 [ 34 ]. While only 27% of the GnRH neurons appear
to be activated by kisspeptin in 8-19-day-old mice; this percentage increases to
44% in 26-33-day-old mice, which may be interpreted as a progressive increase in
GnRH neuron responsiveness to kisspeptin stimulation at puberty [ 32 ]. On the other
hand, the release of inhibitory input contributes signifi cantly to the progressive
increase in GnRH pulsatility observed at puberty. As an example, a recent study in
monkeys shows that infusion of a GABA antagonist (bicuculline) increases GnRH
pulsatility and accelerates menarche in female monkeys [ 35 ]. Interestingly, this
effect was shown to be mediated by kisspeptin secretion and signaling [ 35 ]. This
suggests that the release of GABAergic inhibition of kisspeptin plays a signifi cant
role in the onset of puberty in monkeys.
KISS1R, Puberty, and Pubertal Disorders
The progressive responsiveness of GnRH neurons to the powerful depolarizing
effects of KISS1R during postnatal development suggests that signaling by
KISS1R is a key event in the process driving the hallmark increase in GnRH
pulses during puberty [ 32 ]. The essential role of KISS1R signaling for the onset
of puberty is confi rmed by the phenotype exhibited by humans carrying naturally