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activity of the GnRH/gonadotropin system (
Navarro, Fernandez-
Fernandez, et al., 2004; Navarro, Castellano, et al., 2004; Plant,
Ramaswamy, & Dipietro, 2006; Shahab et al., 2005
);
An increase in the sensitivity to the stimulatory effects of kisspeptin on
GnRH/LH secretion, as mainly documented in rodents (
Castellano,
Navarro, Fernandez-Fernandez, Castano, et al., 2006; Han et al., 2005
);
A heightening of Gpr54 signaling efficiency that seems to be associated
to a state of resistance to desensitization to continuous kisspeptin stim-
ulation (
Han et al., 2005; Roa, Vigo, et al., 2008
); and
An elevation in the number of kisspeptin-positive neurons in the hypo-
thalamus and of their projections to GnRH neurons, which has been
documented mainly in rodents (
Bentsen et al., 2010; Clarkson &
Herbison, 2006
).
Notably, this complex developmental program seems to form a fail-safe
mechanism for the precise timing of puberty, since the GnRH/LH axis
becomes fully responsive to kisspeptin stimulation at much earlier stages
of postnatal development (e.g., neonatal/infantile period) (
Castellano,
Navarro, Fernandez-Fernandez, Castano, et al., 2006; Nazian, 2006
). In
the absence of precise regulatory mechanisms, the latter feature would make
the system especially prone to precocious activation, as very potent gonad-
otropic responses are elicited in infantile rodents by administration of even
low doses of kisspeptin (
Castellano, Navarro, Fernandez-Fernandez,
Castano, et al., 2006
). The relevance of proper kisspeptin signaling for
the precise timing of puberty is reinforced by the observation that pharma-
cological blockade of Gpr54 delays puberty onset in rats (
Pineda et al., 2010
)
and timed ablation of Kiss1 neurons in the juvenile period prevents the
attainment of reproductive competence (
Mayer & Boehm, 2011
).
Despite this compelling evidence, some aspects of the pubertal roles of
kisspeptins remain obscure. For instance, whether the activational program
described above equally applies to the different hypothalamic populations
of Kiss1 neurons is yet to be characterized. In this sense, detailed studies in
rodents have identified two prominent populations of Kiss1 neurons in the
hypothalamus: one located in the arcuate nucleus (ARC) and the other in
the rostral periventricular area of the 3rd ventricle (RP3V) (
Clarkson,
Anglemont de Tassigny, Colledge, Caraty, & Herbison, 2009; Pinilla et al.,
2012
). In other mammals, including primates, Kiss1 neurons are consistently
present in the ARC/infundibular region, but the existence and/or abundance
of a population equivalent to that of the RP3V Kiss1 neurons in rodents are
yet the matter of debate (
Pinilla et al., 2012
). Of note, ARC and RP3V Kiss1