Beyond the GnRH Axis: Kisspeptin Regulation of the Oxytocin System in Pregnancy and Lactation - Kisspeptin Signaling in Reproductive Biology - page 203

concentration of kisspeptin in woman has been reported to increase hugely over the
course of pregnancy, with a 900-fold rise in the fi rst trimester that further increases
to over 7,000-fold in the third trimester. While the circulating kisspeptin that is
found at low concentrations in non-pregnant women (and in men) is likely to be
from either vascular endothelial cells [ 57 ] or adipose tissue [ 58 ], the main source of
circulating kisspeptin during pregnancy is likely to be the placenta, because KISS1
mRNA and kisspeptin protein are detectable in syncytiotrophoblasts in the placental
wall [ 59 ]. The physiological function of elevated kisspeptin during human preg-
nancy is unknown; while it is possible that kisspeptin regulates trophoblast invasion,
a process that is important for embryonic development [ 60 ], we hypothesised that
such elevations in circulating kisspeptin might signal the oxytocin neurons to
prepare for birth and lactation.

Activation of Oxytocin Neurons by Peripheral Kisspeptin
in Non-pregnant Rats

To determine whether circulating kisspeptin might signal the oxytocin neurons to
prepare for birth and lactation, we used an in vivo electrophysiology preparation to
record spontaneous activity from the neurons in the SON of anaesthetised rats. This
preparation causes the least disruption to whole animal physiology, allowing us to
record near-normal neuron activity that can be altered by their intact peripheral and
central inputs. Our work using this preparation was the fi rst to show that neurons in
the SON increase their fi ring rate following IV administration of kisspeptin-10 [ 2 ].
First, extracellular single-unit recordings of action potential fi ring rate were
made from oxytocin neurons in non-pregnant rats across all stages of the estrous
cycle. Intravenous administration of 25

g kisspeptin-10 (which should achieve
similar circulating concentrations of kisspeptin reported at the end of human preg-
nancy [ 57 ]) increases plasma oxytocin levels in the blood of virgin female rats [ 1 ],
and so we administered 25

μ

g IV kisspeptin-10 to investigate whether changes in
oxytocin neuron activity underpin the increased plasma hormone concentration; we
found that this IV dose of kisspeptin-10 caused a robust, short-lived (~5 min)
increase in the fi ring rate of every single oxytocin neuron tested (Fig. 10.2 ). The
increase in fi ring rate following the peripheral kisspeptin injection was rapid, with a
clear increase in fi ring rate within 30 s of administration and the peak rate within
60 s. The majority of the neurons showed a return to basal levels between 5 and
10 min following the injection. Hence, we were able to show that oxytocin neurons
are able to rapidly respond to fl uctuations in circulating kisspeptin, at least in non-
pregnant rats. Importantly, repeated IV injections of kisspeptin-10 every few min-
utes caused a similar increase in fi ring rate, showing that the oxytocin neuron
response does not desensitise over the time course expected for milk-ejection bursts.
Given the short duration of excitation, and the lack of down-regulation of the
response, it is likely that breakdown of kisspeptin (rather than a long deactivation or

μ