High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons
Open accessAbstract
Kisspeptin (Kiss1) and neurokinin B (NKB) neurocircuits are essential for pubertal development and fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (Kiss1(ARH)) co-express Kiss1, NKB, dynorphin and glutamate and are postulated to provide an episodic, excitatory drive to gonadotropin-releasing hormone 1 (GnRH) neurons, the synaptic mechanisms of which are unknown. We characterized the cellular basis for synchronized Kiss1(ARH) neuronal activity using optogenetics, whole-cell electrophysiology, molecular pharmacology and single cell RT-PCR in mice. High-frequency photostimulation of Kiss1(ARH) neurons evoked local release of excitatory (NKB) and inhibitory (dynorphin) neuropeptides, which were found to synchronize the Kiss1(ARH) neuronal firing. The light-evoked synchronous activity caused robust excitation of GnRH neurons by a synaptic mechanism that also involved glutamatergic input to preoptic Kiss1 neurons from Kiss1(ARH) neurons. We propose that Kiss1(ARH) neurons play a dual role of driving episodic secretion of GnRH through the differential release of peptide and amino acid neurotransmitters to coordinate reproductive function.
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Neuropeptide signalling within the arcuate nucleus kisspeptin population has a pivotal role in GnRH pulse generation.
“The model draws on recent experimental work, which demonstrates the pivotal role of neuropeptide signalling within the arcuate nucleus kisspeptin population for GnRH pulse generation 65, 66.”
From Mathematical Modelling of Endocrine Systems (2019) · cites this paper as [66]
The Results show that dynorphin modulates neurokinin B signalling among arcuate kisspeptin neurons, and the Discussion describes peptide-dependent synchronization and an excitatory drive to GnRH neurons (page numbers unavailable). But the Discussion says these neurons “probably” drive pulsatile GnRH secretion; this paper proposes rather than directly demonstrates the role of that signalling in GnRH pulse generation. (LLM, conf=0.84)
Experimental — accuracy not yet measuredNKB functions as an excitatory signal by depolarizing KNDy cells at the postsynaptic site, while coreleased Dyn functions presynaptically to inhibit NKB release.
“with the key mechanistic finding that NKB functions as an excitatory signal by depolarizing KNDy cells at the postsynaptic site, while coreleased Dyn functions presynaptically to inhibit NKB release.”
From The Origin of GnRH Pulse Generation: An Integrative Mathematical-Experimental Approach (2019) · cites this paper as Qiu et al., 2016
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- Authors
- Qiu, J., Nestor, C. C., Zhang, C., Padilla, S. L., Palmiter, R. D., Kelly, M. J., & Rønnekleiv, O. K.
- Affiliations
- Oregon Health & Science University (US)
- Department of Biochemistry, Howard Hughes Medical Institute, University of Washington, Seattle, United States
- Howard Hughes Medical Institute (US)
- Oregon National Primate Research Center (US)
- Corresponding author
- Qiu, Jian
- Kelly, Martin J
- Rønnekleiv, Oline K
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2016-08-23
- Volume
- 5
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC4995096
- OpenAlex
- W2514473526
- Cited by
- 199
- References
- 68
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 25 · 2023: 13 · 2022: 30 · 2021: 28 · 2020: 17 · 2019: 25 · 2018: 25 · 2017: 10 · 2016: 3
- FWCI
- 27.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (R01-NS38809, R01-NS43330, R01-DK68098, F32 DK104366)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- kisspeptin, arcuate nucleus, kisspeptin neurons, neurokinin B, dynorphin, GnRH neurons, neuropeptide release, neuronal synchronization, glutamatergic neurotransmission, pubertal development, fertility, optogenetics
- MeSH terms
- Action Potentials, Animals, Arcuate Nucleus of Hypothalamus, Gonadotropin-Releasing Hormone, Neurons, Neurokinin B, Mice, Electrophysiological Phenomena, Kisspeptins, Real-Time Polymerase Chain Reaction, Optogenetics
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