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Although Kiss1r has yet to be identifi ed in GnRH terminals, this is likely another
site of kisspeptin action because this peptide stimulates GnRH release in vitro from
the median eminence of rats [
144
] and sheep [
86
]. It should be noted, however, that
neither ARC nor RP3V kisspeptin cells in mice [
108
] or rats [
123
] have direct
access to the portal vessels and, as such, are unlikely to act directly on GnRH termi-
nals at the primary capillary bed of the median eminence.
There is also evidence for reciprocal connections within and between these two
kisspeptin populations. The strongest data is for extensive reciprocal connections
among KNDy neurons in a number of species, but there is also data that less abundant
connections occur within the POA kisspeptin population in sheep. There is also
clear evidence that KNDy neurons project to the RP3V of rodents and to some POA
kisspeptin neurons in sheep. Conversely, almost half of the RP3V kisspeptin neu-
rons project to the ARC in mice. It is important to note that the functional signifi -
cance of kisspeptin release at these reciprocal connections is unclear because there
is no evidence that kisspeptin neurons in the ARC or RP3V/POA contain
Kiss1r
.
The other neurotransmitters within ARC KNDy neurons have been postulated to
play a key role in synchronizing this population and driving episodic GnRH secre-
tion. It is thus likely that reciprocal connections within the ARC play an important
functional role, but whether that is true for the more rostral kisspeptin populations
awaits further study.
Finally, although detailed discussion of the functional roles of these kisspeptin
populations is beyond the scope of this chapter, as described elsewhere in this topic
there also appear to be common functional roles for these two kisspeptin popula-
tions. The rostral population is clearly involved in the preovulatory GnRH surge in
many species, and the ARC population has been implicated in the negative feedback
action of gonadal steroids and in possibly synchronizing GnRH neural activity during
episodic secretion. The latter appears to play a key role in the onset of puberty in
rodents, sheep, and primates, although the RP3V population likely contributes to
this process in mice.
This review also identifi ed several important gaps in our understanding of the
neuroanatomy of kisspeptin signaling. The most obvious of these is the paucity of
detailed information on the distribution of
Kiss1r
mRNA and the complete lack of
any data on location of Kiss1r protein. Until more complete anatomical information
is available on the location of these receptors, any conclusions as to physiological
signifi cance of most kisspeptin projections must be considered tentative at best.
Information is also beginning to be developed on extra-hypothalamic kisspeptin
cells and fi bers, but this remains limited to just a few species. Thus, these data need
to be extended to a broader range of species and studies on their functional signifi -
cance developed. Another anatomical issue of importance revolves around identify-
ing inputs to kisspeptin cell bodies. While some data is available on afferents to
ARC and POA/RP3V kisspeptin cell bodies, this information is fragmentary.
A fuller understanding of the complete complement of presynaptic inputs to these,
and other, kisspeptin cells will obviously be important for understanding their neu-
ral control. Finally, kisspeptin cells in the ARC, POA/RP3V, and elsewhere are
likely to play a signifi cant role in the regulation of other physiological systems
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