Beyond the GnRH Axis: Kisspeptin Regulation of the Oxytocin System in Pregnancy and Lactation - Kisspeptin Signaling in Reproductive Biology - page 199

offspring, resulting in the death of the pups. These mice have normal milk production,
as well as normal ductal/glandular epithelium in the mammary gland, and the pups
latch and suckle the nipples but, unlike wild type animals, this fails to induce milk
ejection. Exogenous oxytocin administration in these mice can produce suffi cient
milk let-down to release milk and keep pups alive [ 11 ], highlighting the essential
role for oxytocin in the milk-ejection refl ex.
The Magnocellular Neurosecretory System
Oxytocin is principally synthesised in magnocellular neurons of the supraoptic
nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus and released
from the posterior pituitary gland to act in the periphery. The PVN contains magno-
cellular neurons that synthesise either oxytocin, or the closely related peptide vaso-
pressin, and parvocellular neurons that contain a range of other peptide hormones
and project to the median eminence to control anterior pituitary hormone secretion,
as well as to other brain regions. By contrast to the PVN, the SON contains only
magnocellular oxytocin and vasopressin neurons, which project a single axon cau-
dally and medially to collect in the hypothalamo-neurohypophysial tract. These
axons travel through the internal zone of the median eminence to the posterior pitu-
itary gland (the neurohypophysis), where they end in several thousand neurosecre-
tory axon swellings and terminals, fi lled with dense-core granules (neurosecretory
vesicles) containing oxytocin (or vasopressin) [ 17 ]. Exocytosis of the neurosecre-
tory vesicles occurs in response to invasion from action potentials, and once released
into the extracellular space, oxytocin enters the general circulation by diffusion
through fenestrated capillaries in the posterior pituitary gland [ 18 ]. The axon termi-
nals in the posterior pituitary gland cannot maintain intrinsic repetitive fi ring [ 19 ],
and so hormone secretion is principally determined by the frequency and pattern of
action potentials initiated at the cell bodies. Nevertheless, various factors can modu-
late the release from magnocellular neuron terminals, including ionic conditions
[ 20 ], purines [ 21 ] and neuropeptides [ 22 ].
Firing Patterns of Oxytocin Neurons
The profi le of oxytocin secretion from the posterior pituitary gland is co-ordinated
by the pattern of action potential discharge at the oxytocin cell bodies [ 23 ].
Nevertheless, the axon terminals in the posterior pituitary gland actively modulate
the secretory response to action potential invasion by increasing the effi ciency of
stimulus-secretion coupling at higher fi ring rates so that each action potential
releases more oxytocin per action potential at high action potential frequencies than at
low frequencies [ 24 ]. As a result, when oxytocin neurons respond to stimulation with
a linear increase in fi ring rate, the hormone output from the posterior pituitary gland is
facilitated as the frequency of stimulation increases [ 24 ]. This frequency-facilitation