Local kisspeptin excitation of rat oxytocin neurones in late pregnancy

Abstract

The hormone, oxytocin, is synthesised by magnocellular neurones of the supraoptic and paraventricular nuclei and is released from the posterior pituitary gland into the circulation to trigger uterine contractions during parturition. Kisspeptin fibre density increases around the supraoptic nucleus over pregnancy and intracerebroventricular kisspeptin excites oxytocin neurones only in late pregnancy. However, the mechanism of this excitation is unknown. Here, we found that microdialysis administration of kisspeptin into the supraoptic nucleus consistently increased the action potential (spike) firing rate of oxytocin neurones in urethane‐anaesthetised late‐pregnant rats (gestation day 18–21) but not in non‐pregnant rats. Hazard analysis of action potential firing showed that kisspeptin specifically increased the probability of another action potential firing immediately after each action potential (post‐spike excitability) in late‐pregnant rats. Patch‐clamp electrophysiology in hypothalamic slices showed that bath application of kisspeptin did not affect action potential frequency or baseline membrane potential in supraoptic nucleus neurones. Moreover, kisspeptin superfusion did not affect the frequency or amplitude of excitatory postsynaptic currents or inhibitory postsynaptic currents in supraoptic nucleus neurones. Taken together, these studies suggest that kisspeptin directly activates oxytocin neurones in late pregnancy, at least in part, via increased post‐spike excitability. Key points Oxytocin secretion is triggered by action potential firing in magnocellular neurones of the hypothalamic supraoptic and paraventricular nuclei to induce uterine contractions during birth. In late pregnancy, kisspeptin expression increases in rat periventricular nucleus neurones that project to the oxytocin system. Here, we show that intra‐supraoptic nucleus administration of kisspeptin increases the action potential firing rate of oxytocin neurones in anaesthetised late‐pregnant rats, and that the increased firing rate is associated with increased oxytocin neurone excitability immediately after each action potential. By contrast, kisspeptin superfusion of hypothalamic slices did not affect the activity of supraoptic nucleus neurones or the strength of local synaptic inputs to supraoptic nucleus neurones. Hence, kisspeptin might activate oxytocin neurons in late pregnancy by transiently increasing oxytocin neuron excitability after each action potential.

Central kisspeptin does not affect ERK1/2 or p38 phosphorylation in oxytocin neurons of late-pregnant rats

“…Lack of kisspeptin induction of ERK1/2 or p38 phosphorylation in afferent inputs to the oxytocin system While our recent ndings showed that kisspeptin excites oxytocin neurons in late pregnancy, in part, by a direct action of kisspeptin on oxytocin neurons, our ndings also suggested that activation of afferent inputs might also contribute to the excitation (Abbasi et al 2022). Therefore, we mapped kisspeptininduced ERK1/2 and p38 phosphorylation in brain areas that project to the oxytocin system and express Kiss1R and NPFFR (LC, DRN, OVLT, SFO, AVPe, ARC) (Lee et al 1999 Herbison et al 2010).…”

“…We have recently shown that kisspeptin excites oxytocin neurons in late pregnancy, in part, by a direct action on oxytocin neurons (Abbasi et al 2022). The present study revealed that ICV kisspeptin did not induce ERK1/2 or p38 phosphorylation in oxytocin neurons of non-pregnant or late-pregnant rats when administered at a dose that increases oxytocin neuron ring rate in late-pregnant rats (Seymour et al 2017).…”

“…Hence, PI3K-Akt might mediate the direct effects of kisspeptin on oxytocin neurons in late pregnancy. While kisspeptin excites GnRH neurons by activating non-speci c cation channels and inhibiting potassium channels (Liu et al 2008), it does not appear to excite oxytocin neurons via these channels because baseline holding currents are unchanged by kisspeptin superfusion in SON brain slices (Abbasi et al 2022). Alternatively, or additionally, kisspeptin activation of oxytocin neurons might not be mediated by Kiss1R.…”

“…While the same caveats apply to the lack of ERK1/2 or p38 phosphorylation in their afferent inputs as apply to the oxytocin neuron themselves, a further possibility is that kisspeptin might enhance excitatory synaptic transmission via presynaptic actions on oxytocin neurons afferent inputs. If active, this mechanism does not involve local glutamatergic or GABAergic inputs to oxytocin neurons, which are unaffected by kisspeptin in brain slices from non-pregnant and late-pregnant rats (Abbasi et al 2022). Therefore, the most likely candidate might be the NTS noradrenergic input, which is activated at parturition (Meddle et al 2000), releasing noradrenaline (Herbison et al 1997) to excite oxytocin neurons via α 1 -adrenoreceptors (Douglas et al 2001).…”

“…Kisspeptin neurons also project to the SON (Desroziers et al 2010) and kisspeptin bre density increases around oxytocin neurons during pregnancy (Seymour et al 2017). Furthermore, intracerebroventricular (ICV) kisspeptin excites oxytocin neurons only in late pregnancy (Seymour et al 2017) and we have recently shown that this excitation is mediated by direct effects on oxytocin neurons as well as by enhancement of excitatory afferent signalling (Abbasi et al 2022).…”