Biology Reference
In-Depth Information
Site of Action of Kisspeptin
Kisspeptin Actions in the Brain
Kisspeptin is thought to act in the hypothalamus and results in GnRH release, which
in turn acts on the pituitary gland to cause gonadotropin release. This mode of
action is supported by several lines of evidence. First, the stimulatory effects of
kisspeptin on gonadotropin release are attenuated in the presence of a GnRH antag-
onist in a number of species, including ewes, rats, mice, and primates [
1
,
5
,
16
,
29
-
31
]. Second, peripherally administered kisspeptin-54 elicits c-fos activation in
60% of GnRH neurons in the hypothalamus [
1
]. Third, kisspeptin treatment leads to
a rise in GnRH levels in the CSF of sheep [
14
,
25
]. Fourth, patch clamp studies
demonstrate that kisspeptin activates GnRH neuronal fi ring in brain slices from
adult female proestrus mice [
32
].
Anatomical data also support the notion that kisspeptin acts on GnRH neurons in
the brain. In the rat, more than 75% of GnRH neurons co-express kisspeptin recep-
tor mRNA [
31
], and this has also been shown for several other species. In the rodent
brain, there are two high density populations of kisspeptin immunoreactive cells in
the hypothalamus; fi rstly, in the periventricular continuum of cells within the rostral
part of the third ventricle (which includes the antero-ventral periventricular nucleus
[AVPV] and the periventricular nucleus [PeN]), and secondly, in the arcuate nucleus
(ARC). It has been shown in rodents that kisspeptin immunoreactive nerve elements
directly adjoin GnRH immunoreactive nerve elements in the median eminence [
33
].
Hence, kisspeptin may in part stimulate GnRH release from GnRH neurons by non-
synaptic axo-axonal interactions at the median eminence [
33
]. In possible support
for this, incubation of rat hypothalamic explants with kisspeptin-10 stimulated the
release of GnRH [
4
].
The brain is protected from circulating substances in the peripheral blood by
tight endothelial junctions forming the blood-brain barrier. The circulating blood
comes in contact with the brain only at specifi c areas, including the median emi-
nence and organum vasculosum of the lamina terminalis (OVLT). GnRH neurons
project axons to the median eminence, from where they secrete GnRH into the
portal vasculature to control pituitary gonadotropin release. A sub-population of
GnRH neurons located in the rostral preoptic area possesses complex branching
dendritic branches, which fi ll the OVLT [
34
]. It was shown that these GnRH neu-
rons in the OVLT are susceptible to stimulation by kisspeptin [
34
]. Therefore,
kisspeptin may also stimulate GnRH release via interaction with GnRH neuronal
fi bers at the OVLT and/or the median eminence [
34
].
In the rat, kisspeptin neurons are present in the hypothalamic ARC and the
AVPV. To investigate the direct site of action of kisspeptin in the brain, administra-
tion of kisspeptin-10 into the region of the ARC or the medial preoptic area (which
includes the AVPV) was assessed in estrogen-replaced ovariectomized adult female
rats. Both intra-ARC and intra-mPOA administration of kisspeptin-10, at 1, 10, and
Search WWH ::
Custom Search