Estradiol elicits distinct firing patterns in arcuate nucleus kisspeptin neurons of females through altering ion channel conductances
Hypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1ARH) neurons are responsible for the pulsatile release of gonadotropin-releasing hormone (GnRH). In females, the behavior of Kiss1ARH neurons, expressing Kiss1, neurokinin B (NKB)...
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eLife Sciences Publications Ltd
2024-12-01
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| Online Access: | https://elifesciences.org/articles/96691 |
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| author | Jian Qiu Margaritis Voliotis Martha A Bosch Xiao Feng Li Larry S Zweifel Krasimira Tsaneva-Atanasova Kevin T O'Byrne Oline K Rønnekleiv Martin J Kelly |
| author_facet | Jian Qiu Margaritis Voliotis Martha A Bosch Xiao Feng Li Larry S Zweifel Krasimira Tsaneva-Atanasova Kevin T O'Byrne Oline K Rønnekleiv Martin J Kelly |
| author_sort | Jian Qiu |
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| description | Hypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1ARH) neurons are responsible for the pulsatile release of gonadotropin-releasing hormone (GnRH). In females, the behavior of Kiss1ARH neurons, expressing Kiss1, neurokinin B (NKB), and dynorphin (Dyn), varies throughout the ovarian cycle. Studies indicate that 17β-estradiol (E2) reduces peptide expression but increases Slc17a6 (Vglut2) mRNA and glutamate neurotransmission in these neurons, suggesting a shift from peptidergic to glutamatergic signaling. To investigate this shift, we combined transcriptomics, electrophysiology, and mathematical modeling. Our results demonstrate that E2 treatment upregulates the mRNA expression of voltage-activated calcium channels, elevating the whole-cell calcium current that contributes to high-frequency burst firing. Additionally, E2 treatment decreased the mRNA levels of canonical transient receptor potential (TPRC) 5 and G protein-coupled K+ (GIRK) channels. When Trpc5 channels in Kiss1ARH neurons were deleted using CRISPR/SaCas9, the slow excitatory postsynaptic potential was eliminated. Our data enabled us to formulate a biophysically realistic mathematical model of Kiss1ARH neurons, suggesting that E2 modifies ionic conductances in these neurons, enabling the transition from high-frequency synchronous firing through NKB-driven activation of TRPC5 channels to a short bursting mode facilitating glutamate release. In a low E2 milieu, synchronous firing of Kiss1ARH neurons drives pulsatile release of GnRH, while the transition to burst firing with high, preovulatory levels of E2 would facilitate the GnRH surge through its glutamatergic synaptic connection to preoptic Kiss1 neurons. |
| format | Article |
| id | doaj-art-c2ef4d1e60eb40988f1c152901056be3 |
| institution | DOAJ |
| issn | 2050-084X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj-art-c2ef4d1e60eb40988f1c152901056be32025-08-20T02:52:41ZengeLife Sciences Publications LtdeLife2050-084X2024-12-011310.7554/eLife.96691Estradiol elicits distinct firing patterns in arcuate nucleus kisspeptin neurons of females through altering ion channel conductancesJian Qiu0https://orcid.org/0000-0002-4988-8587Margaritis Voliotis1https://orcid.org/0000-0001-6488-7198Martha A Bosch2Xiao Feng Li3Larry S Zweifel4https://orcid.org/0000-0003-3465-5331Krasimira Tsaneva-Atanasova5https://orcid.org/0000-0002-6294-7051Kevin T O'Byrne6https://orcid.org/0000-0002-2548-4182Oline K Rønnekleiv7https://orcid.org/0000-0003-1841-4386Martin J Kelly8https://orcid.org/0000-0002-8633-2510Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, United StatesDepartment of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom; Living Systems Institute, University of Exeter, Exeter, United KingdomDepartment of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, United StatesDepartment of Women and Children’s Health, School of Life Course and Population Sciences, King’s College London, London, United KingdomDepartment of Psychiatry and Behavioral Sciences, University of Washington, Seattle, United States; Depatment of Pharmacology, University of Washington, Seattle, United StatesDepartment of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom; Living Systems Institute, University of Exeter, Exeter, United KingdomDepartment of Women and Children’s Health, School of Life Course and Population Sciences, King’s College London, London, United KingdomDepartment of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, United States; Division of Neuroscience, Oregon National Primate Research Center, Beaverton, United StatesDepartment of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, United States; Division of Neuroscience, Oregon National Primate Research Center, Beaverton, United StatesHypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1ARH) neurons are responsible for the pulsatile release of gonadotropin-releasing hormone (GnRH). In females, the behavior of Kiss1ARH neurons, expressing Kiss1, neurokinin B (NKB), and dynorphin (Dyn), varies throughout the ovarian cycle. Studies indicate that 17β-estradiol (E2) reduces peptide expression but increases Slc17a6 (Vglut2) mRNA and glutamate neurotransmission in these neurons, suggesting a shift from peptidergic to glutamatergic signaling. To investigate this shift, we combined transcriptomics, electrophysiology, and mathematical modeling. Our results demonstrate that E2 treatment upregulates the mRNA expression of voltage-activated calcium channels, elevating the whole-cell calcium current that contributes to high-frequency burst firing. Additionally, E2 treatment decreased the mRNA levels of canonical transient receptor potential (TPRC) 5 and G protein-coupled K+ (GIRK) channels. When Trpc5 channels in Kiss1ARH neurons were deleted using CRISPR/SaCas9, the slow excitatory postsynaptic potential was eliminated. Our data enabled us to formulate a biophysically realistic mathematical model of Kiss1ARH neurons, suggesting that E2 modifies ionic conductances in these neurons, enabling the transition from high-frequency synchronous firing through NKB-driven activation of TRPC5 channels to a short bursting mode facilitating glutamate release. In a low E2 milieu, synchronous firing of Kiss1ARH neurons drives pulsatile release of GnRH, while the transition to burst firing with high, preovulatory levels of E2 would facilitate the GnRH surge through its glutamatergic synaptic connection to preoptic Kiss1 neurons.https://elifesciences.org/articles/96691kisspeptin neuron17beta-estradiolion channelssynchronous firingburst firingmathematical modeling |
| spellingShingle | Jian Qiu Margaritis Voliotis Martha A Bosch Xiao Feng Li Larry S Zweifel Krasimira Tsaneva-Atanasova Kevin T O'Byrne Oline K Rønnekleiv Martin J Kelly Estradiol elicits distinct firing patterns in arcuate nucleus kisspeptin neurons of females through altering ion channel conductances eLife kisspeptin neuron 17beta-estradiol ion channels synchronous firing burst firing mathematical modeling |
| title | Estradiol elicits distinct firing patterns in arcuate nucleus kisspeptin neurons of females through altering ion channel conductances |
| title_full | Estradiol elicits distinct firing patterns in arcuate nucleus kisspeptin neurons of females through altering ion channel conductances |
| title_fullStr | Estradiol elicits distinct firing patterns in arcuate nucleus kisspeptin neurons of females through altering ion channel conductances |
| title_full_unstemmed | Estradiol elicits distinct firing patterns in arcuate nucleus kisspeptin neurons of females through altering ion channel conductances |
| title_short | Estradiol elicits distinct firing patterns in arcuate nucleus kisspeptin neurons of females through altering ion channel conductances |
| title_sort | estradiol elicits distinct firing patterns in arcuate nucleus kisspeptin neurons of females through altering ion channel conductances |
| topic | kisspeptin neuron 17beta-estradiol ion channels synchronous firing burst firing mathematical modeling |
| url | https://elifesciences.org/articles/96691 |
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