The Development of Kisspeptin Circuits in the Mammalian Brain - Kisspeptin Signaling in Reproductive Biology - page 227

female mice were either ovariectomized (OVX) or sham treated on PND 15 and
killed on either PND 30 or PND 60. Mice that were OVX on PND 15 had dramati-
cally reduced levels of kisspeptin in the AVPV/PeN later in adulthood, suggesting
that the primary cause of the developmental kisspeptin increase is due to ovarian sex
steroid secretion [ 62 ]. This was supported by the observation that estrogen replace-
ment in OVX animals from either PND 15-30 or PND 22-30 rescues kisspeptin
expression when examined at PND 30 [ 62 ]. Thus, kisspeptin neurons are sensitive
to ovarian steroids peri-pubertally, which is not surprising given their robust regula-
tion by sex steroids in adulthood. It is currently unknown if kisspeptin neurons,
however, are responsive to E 2 at the fi rst time of visible protein expression (PND 15)
or mRNA expression (PND 10), or if OVX at earlier time periods has a more per-
manent effect on the development of kisspeptin expression.
Several studies have used aromatase knockout (ArKO) mice to examine the
effects of E 2 signaling on kisspeptin neuron development. One study reported a
complete elimination of kisspeptin expression in the AVPV/PeN of adult female
ArKO mice [ 62 ]. However, E 2 was not replaced in these mice prior to sacrifi ce, and
it was therefore unclear if the absence of AVPV/PeN kisspeptin cells in ArKO
females mirrored a chronically OVX condition (since removal of E 2 via OVX in
adulthood reduces AVPV/PeN kisspeptin synthesis). More recently, another study
looked at kisspeptin cells in ArKO mice that were given E 2 in adulthood. This study
found that AVPV/PeN kisspeptin cells were in fact present in adult ArKO mice after
E 2 -treatment. However, surprisingly, the sex difference in kisspeptin cell number
was eliminated in these E 2 -treated ArKO mice [ 92 ]. But, instead of ArKO males
exhibiting high kisspeptin levels similar to that of wild-type (WT) females, as would
be predicted due to the lack of E 2 -signaling in these males during the postnatal criti-
cal period, AVPV/PeN kisspeptin cell number was instead intermediate in level in
ArKOs of both sexes, being signifi cantly lower than in normal WT females and
signifi cantly higher than in normal WT males [ 92 ]. This fi nding suggests that E 2
during development may normally actively contribute to complete feminization of
the AVPV/PeN kisspeptin system in females, although when and how this would
occur is unknown.
A similar story has emerged concerning the development of the AVPV/PeN kis-
speptin system in hypogonadal ( hpg ) mice. Hypogonadal mice possess a deletion in
the Gnrh gene and therefore do not secrete GnRH or gonadal sex steroids [ 93 ]. In
female hpg mice, AVPV/PeN kisspeptin-ir cell number during development never
reaches the level of WT females and is similar to that of hpg males (i.e., the normal
kisspeptin sex difference is absent in hpg mice) [ 94 ]. Similarly, Kiss1 mRNA
expression in pubertal hpg females is decreased compared to that of WT females,
and sexually dimorphic Kiss1 expression is eliminated in hpg mice [ 94 ]. Hormone
replacement was not compared in pubertal hpg females and males in this particular
study and may be critical to fully interpret the results. Interestingly though, 1 week
of E 2 replacement in adult hpg females did not increase AVPV/PeN kisspeptin
protein levels to WT female levels, suggesting that gonadal sex steroids may be
required at some time during development in order for AVPV/PeN kisspeptin
expression to fully mature [ 94 ].