Modulation of pulsatile GnRH dynamics across the ovarian cycle via changes in the network excitability and basal activity of the arcuate kisspeptin network
- University of Exeter, United Kingdom
- King's College London, United Kingdom
- Exeter University, United Kingdom
Abstract
Pulsatile GnRH release is essential for normal reproductive function. Kisspeptin secreting neurons found in the arcuate nucleus, known as KNDy neurons for co-expressing neurokinin B, and dynorphin, drive pulsatile GnRH release. Furthermore, gonadal steroids regulate GnRH pulsatile dynamics across the ovarian cycle by altering KNDy neurons' signalling properties. However, the precise mechanism of regulation remains mostly unknown. To better understand these mechanisms we start by perturbing the KNDy system at different stages of the estrous cycle using optogenetics. We find that optogenetic stimulation of KNDy neurons stimulates pulsatile GnRH/LH secretion in estrous mice but inhibits it in diestrous mice. These in-vivo results in combination with mathematical modelling suggest that the transition between estrus and diestrus is underpinned by well-orchestrated changes in neuropeptide signalling and in the excitability of the KNDy population controlled via glutamate signalling. Guided by model predictions, we show that blocking glutamate signalling in diestrous animals inhibits LH pulses, and that optic stimulation of the KNDy population mitigates this inhibition. In estrous mice, disruption of glutamate signalling inhibits pulses generated via sustained low-frequency optic stimulation of the KNDy population, supporting the idea that the level of network excitability is critical for pulse generation. Our results reconcile previous puzzling findings regarding the estradiol-dependent effect that several neuromodulators have on the GnRH pulse generator dynamics. Therefore, we anticipate our model to be a cornerstone for a more quantitative understanding of the pathways via which gonadal steroids regulate GnRH pulse generator dynamics. Finally, our results could inform useful repurposing of drugs targeting the glutamate system in reproductive therapy.
Data availability
The data and the code are publicly available via the following open access repositories:http://doi.org/doi:10.18742/RDM01-750https://git.exeter.ac.uk/mv286/kndy-parameter-inference.git
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Modulation of pulsatile GnRH dynamics along the reproductive cycle - the role of excitability within the arcuate kisspeptin networkKing College London Figshare, http://doi.org/doi:10.18742/RDM01-750.
Article and author information
Author details
Margaritis Voliotis
Krasimira Tsaneva-Atanasova
Funding
Engineering and Physical Sciences Research Council (EP/N014391/1)
- Margaritis Voliotis
- Krasimira Tsaneva-Atanasova
Biotechnology and Biological Sciences Research Council (BB/S000550/1)
- Margaritis Voliotis
- Xiao Feng Li
- Kevin O’Byrne
- Krasimira Tsaneva-Atanasova
Biotechnology and Biological Sciences Research Council (BB/S001255/1)
- Margaritis Voliotis
- Xiao Feng Li
- Kevin O’Byrne
- Krasimira Tsaneva-Atanasova
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal procedures performed were approved by the Animal Welfare and Ethical Review Body Committee at King's College London (PP4006193 ) and conducted in accordance with the UK Home Office Regulations.
Copyright
© 2021, Voliotis et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Modulation of pulsatile GnRH dynamics across the ovarian cycle via changes in the network excitability and basal activity of the arcuate kisspeptin network
eLife 10:e71252.
https://doi.org/10.7554/eLife.71252
Further reading
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By influencing calcium homeostasis, local protein synthesis and the endoplasmic reticulum, a small protein called Rab10 emerges as a crucial cytoplasmic regulator of neuropeptide secretion.
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