Kisspeptin: a new peptidergic system regulating oxytocin neurons and their reproductive plasticity in the hypothalamo-neurohypophysial system.

Abstract

In mammals, oxytocin (OT) release from neurohypophysial terminals during pregnancy and lactation is pulsatile, reflecting a coordinated burst firing from parent magnocellular OT neurons in the hypothalamic supraoptic (SON) and paraventricular nuclei (Poulain & Wakerley, 1982). Synchronized electrical bursting insures that OT receptors on uterine smooth muscle (for labour contractions) and the mammary gland myoepithelium (for milk ejection) avoid desensitization, maximizing OT's effects. Investigators have long demonstrated a significant plasticity in many aspects of this system that commence in late pregnancy and persist to lactation – changes suspected to play roles in developing these coordinated bursts (Theodosis et al. 2008; Armstrong, 2015). Electron microscopic investigations revealed that astrocyte processes withdraw from between OT neurons and dendrites during lactation, allowing an increase in close neuronal membrane appositions and a change in the number of excitatory and inhibitory synapses. These changes first appear in late pregnancy, and are thought to be programmed by steroid hormone changes, namely the precipitous drop in progesterone in late pregnancy. This morphological plasticity correlates with alterations in the synaptic and presynaptic actions of both glutamate and GABA on OT neurons. Other significant changes during late pregnancy and lactation that are specific to OT neurons include calcium-dependent afterhyperpolarizations that would modulate bursting patterns, and a significant upregulation in mitogen-activated protein kinase/extracellular signal-related kinase activity. Some of the GABAergic and glutamatergic inputs to magnocellular nuclei come from nearby neurons. In the SON, for example, the surrounding perinuclear zone (PZ) provides both types of inputs, and is an area thought to mediate the selective inhibition of vasopressin (VP) neurons to hypertension. This region has diverse morphological cell types, and receives inputs from regions known to affect magnocellular function, such as the diagonal band of Broca and the septum, as well as from within the hypothalamus itself. However, a specific role of this region in modulating OT neuronal activity has not previously been demonstrated. In this issue of The Journal of Physiology, Seymour et al. (2017) describe hypothalamic periventricular kisspeptin neurons that show significant plasticity during late pregnancy. Kisspeptin, a product of the KiSS-1 gene, is a relatively newly discovered peptide, previously implicated in the control of gonadotropin releasing hormone, but also with significant tumour suppressive actions (Murphy, 2005). In the brain, the kisspeptin periventricular hypothalamic neurons have widespread connections, including to and around the SON and paraventricular nuclei, areas controlling the peripheral release of OT and VP. In the present study, a striking increase in the density of axons within the PZ of the SON (but not in the SON itself) containing kisspeptin-like immunoreactivity was found during late pregnancy, and this was correlated with an upregulation of kisspeptin expression in the rostral periventricular hypothalamic neurons that project to the PZ. Furthermore, this increase appears specific to that cell group, as arcuate nucleus kisspeptin neurons are dramatically downregulated in the same period. These results were coincident with a significant ability of centrally administered kisspeptin to excite OT, but not VP neurons, in late pregnancy. Although mRNA for a kisspeptin receptor, Kiss1R, was found weakly localized to the PZ–SON area, its expression was not increased during late pregnancy, suggesting an upregulation of receptor numbers does not mediate this increased excitation. Indeed, the precise target of the centrally administered kisspeptin was not determined in this study, and as Seymour et al. (2017) suggest, it remains possible that its actions on OT neurons were not mediated by the Kiss1R, but possibly by related peptide receptors, or, by amplification of the Kiss1R signaling pathway. There are other questions that await further research for answers. Is kisspeptin critical for the activation of OT neurons during late pregnancy and lactation, and particularly, do its actions influence the synchronous bursting of these neurons and the consequent pulsatile OT release? Does stimulation of these neurons in the rostral periventricular area reproduce the state-dependent effects of centrally applied kisspeptin on OT neurons, and if so, is this mediated through the PZ? Are PZ neurons directly sensitive to kisspeptin? If so, what is their neurotransmitter phenotype, and are they among the PZ neurons that directly innervate SON neurons? Despite the above caveats, the novel results of this paper demonstrate for the first time a reproductive state-related plasticity in a defined system impacting on OT neurons, the periventricular-to-PZ kisspeptin projection. Whereas previous studies over the past four decades have demonstrated multiple types of neuronal and glial plasticity related to OT neurons during pregnancy and lactation, none have indicated this type of plasticity in a specifically located population of neurons thought to regulate OT neuron activity. Seymour et al. (2017) once again train focus on the PZ as an area potentially critical for integrating signals destined to impact VP and OT release through its locally connecting neurons, whether they be GABAergic, glutamatergic, or other cell types providing neuroactive inputs to the SON.