Interactions Between Kisspeptins and Neurokinin B - Kisspeptin Signaling in Reproductive Biology - page 328

receptor, KOR) [ 102 , 103 ], and its expression in KNDy neurons seems to be marginal
[ 56 , 59 ]. These fi ndings allude to intermediate neurons as the primary site of action
of dynorphin in the context of kisspeptin release, which, allegedly, would play a
substantial role by increasing the turnaround time of the inhibitory signal before act-
ing back on KNDy neurons, therefore allowing for the appearance of a kisspeptin
pulse. Of note, as research on the characterization of KNDy neurons advances, new
co-transmitters emerge, which, in the near future, may make the descriptive term
“KNDy” obsolete. In this vein, glutamate and glutamate receptors, also described in
KNDy neurons [ 104 ], may constitute additional autosynaptic regulatory loops [ 82 ,
104 , 105 ] to “fi ne-tune” kisspeptin release (Fig. 15.4 ). It has been speculated that
this or a similar mechanism may be involved in the attenuation of the severe repro-
ductive phenotype of Tacr3 null mice compared to humans described recently by
Yang and colleagues [ 14 , 106 ]. Moreover, recent studies also suggest an action
(direct and indirect) of GnRH itself on KNDy neurons to, eventually, modulate
GnRH release [ 107 ]; however, this contention requires further research. For instance,
the presence of the GnRH receptor in KNDy neurons has yet to be demonstrated.
Control of Puberty Onset
GnRH release undergoes a series of developmental changes, progressing from an
activated neonatal period, followed by a dormant stage during the infantile and juve-
nile ages, to puberty onset, which is characterized by the appearance of GnRH
pulses with increasing amplitude and frequency. A number of central and peripheral
factors have been posed to mediate this awakening of the reproductive axis; how-
ever, exactly what triggers puberty onset remains elusive.
In recent years, hypothalamic kisspeptin has become a likely candidate to serve
as a gatekeeper of puberty onset. Kisspeptin is the most potent secretagogue of
GnRH described to date [ 5 ], and compelling evidence shows that Kiss1 expression
and synaptic contacts between Kiss1 neurons in the hypothalamus increase at the
time of puberty onset in rodents [ 92 , 108 , 109 ], suggesting that hypothalamic Kiss1
neurons play an important role during this maturational process [ 110 ]. Furthermore,
chronic administration of kisspeptin to prepubertal female rats advances puberty
onset [ 111 ], which is prevented in the presence of a kisspeptin antagonist [ 112 ]. In
this context, if we assume that NKB has a role in the control of kisspeptin release at
the onset of puberty, we could expect that impairments in the NKB/NK3R system
would directly translate into disorders in the timing of puberty. Indeed, as men-
tioned previously, a number of studies have documented impuberism associated
with hypogonadotropic hypogonadism (HH) in humans bearing inactivating muta-
tions in the genes encoding NKB and NK3R, which has been partially recapitulated
in Tacr3 knockout mice. To note, Tac2 / Tacr3 expression in the hypothalamus of rats
(and markedly Tacr3 in the ARC) increases prior to puberty onset [ 22 , 40 ], appar-
ently anticipating the increase of kisspeptin immunoreactivity reported in the rostral
periventricular area of the hypothalamus in prepubertal female mice [ 113 ].