The cryptic gonadotropin-releasing hormone neuronal system of human basal ganglia

  1. Katalin Skrapits  Is a corresponding author
  2. Miklós Sárvári
  3. Imre Farkas
  4. Balázs Göcz
  5. Szabolcs Takács
  6. Éva Rumpler
  7. Viktória Váczi
  8. Csaba Vastagh
  9. Gergely Rácz
  10. András Matolcsy
  11. Norbert Solymosi
  12. Szilárd Póliska
  13. Blanka Tóth
  14. Ferenc Erdélyi
  15. Gábor Szabó
  16. Michael D Culler
  17. Cecile Allet
  18. Ludovica Cotellessa
  19. Vincent Prévot
  20. Paolo Giacobini
  21. Erik Hrabovszky  Is a corresponding author
  1. Institute of Experimental Medicine, Hungary
  2. Semmelweis University, Hungary
  3. University of Veterinary Medicine, Hungary
  4. University of Debrecen, Faculty of Medicine, Hungary
  5. Budapest University of Technology and Economics, Hungary
  6. Amolyt Pharma, United States
  7. University of Lille, France
  8. Univ. Lille, Inserm, France
  9. Université de Lille, France

Abstract

Human reproduction is controlled by ~2,000 hypothalamic gonadotropin-releasing hormone (GnRH) neurons. Here we report the discovery and characterization of additional ~150,000-200,000 GnRH-synthesizing cells in the human basal ganglia and basal forebrain. Nearly all extrahypothalamic GnRH neurons expressed the cholinergic marker enzyme choline acetyltransferase. Similarly, hypothalamic GnRH neurons were also cholinergic both in embryonic and adult human brains. Whole-transcriptome analysis of cholinergic interneurons and medium spiny projection neurons laser-microdissected from the human putamen showed selective expression of GNRH1 and GNRHR1 autoreceptors in the cholinergic cell population and uncovered the detailed transcriptome profile and molecular connectome of these two cell types. Higher-order non-reproductive functions regulated by GnRH under physiological conditions in the human basal ganglia and basal forebrain require clarification. The role and changes of GnRH/GnRHR1 signaling in neurodegenerative disorders affecting cholinergic neurocircuitries, including Parkinson's and Alzheimer's diseases, need to be explored.

Data availability

RNA sequencing files are available in BioProject with the accession number PRJNA680536.

The following data sets were generated

Article and author information

Author details

  1. Katalin Skrapits

    Laboratory of Reproductive Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
    For correspondence
    skrapits.katalin@koki.hu
    Competing interests
    The authors declare that no competing interests exist.
  2. Miklós Sárvári

    Laboratory of Reproductive Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  3. Imre Farkas

    Laboratory of Reproductive Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  4. Balázs Göcz

    Laboratory of Reproductive Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  5. Szabolcs Takács

    Laboratory of Reproductive Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  6. Éva Rumpler

    Laboratory of Reproductive Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  7. Viktória Váczi

    Laboratory of Reproductive Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  8. Csaba Vastagh

    Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  9. Gergely Rácz

    1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  10. András Matolcsy

    1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  11. Norbert Solymosi

    Centre for Bioinformatics, University of Veterinary Medicine, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1783-2041
  12. Szilárd Póliska

    Department of Biochemistry and Molecular Biology, University of Debrecen, Faculty of Medicine, Debrecen, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  13. Blanka Tóth

    Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  14. Ferenc Erdélyi

    Department of Gene Technology and Developmental Biology, Institute of Experimental Medicine, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  15. Gábor Szabó

    Department of Gene Technology and Developmental Biology, Institute of Experimental Medicine, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  16. Michael D Culler

    -, Amolyt Pharma, Newton, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Cecile Allet

    Inserm U 1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, University of Lille, Lille, France
    Competing interests
    The authors declare that no competing interests exist.
  18. Ludovica Cotellessa

    Inserm, CHU Lille, U1172, LilNCog - Lille Neuroscience & Cognition, F-59000, Univ. Lille, Inserm, Lille, France
    Competing interests
    The authors declare that no competing interests exist.
  19. Vincent Prévot

    Inserm, CHU Lille, U1172, LilNCog - Lille Neuroscience & Cognition, F-59000, Univ. Lille, Inserm, Lille, France
    Competing interests
    The authors declare that no competing interests exist.
  20. Paolo Giacobini

    Institut National de la Santé et de la Recherche Médicale, Université de Lille, Lille, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3075-1441
  21. Erik Hrabovszky

    Laboratory of Reproductive Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
    For correspondence
    hrabovszky.erik@koki.hu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6927-0015

Funding

National Science Foundation of Hungary (K128317)

  • Erik Hrabovszky

National Science Foundation of Hungary (PD134837)

  • Katalin Skrapits

Hungarian Brain Research Program (2017-1.2.1-NKP- 2017-00002)

  • Erik Hrabovszky

Institut National de la Santé et de la Recherche Médicale (U1172)

  • Vincent Prévot
  • Paolo Giacobini

Agence Nationale de la Recherche (ANR-19-CE16-0021-02)

  • Paolo Giacobini

Inserm Cross-Cutting Scientific Program (HuDeCa)

  • Paolo Giacobini

NRDI Fund, TKP2020 IES (BME-IE-BIO)

  • Blanka Tóth

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Margaret M McCarthy, University of Maryland School of Medicine, United States

Ethics

Animal experimentation: Experiments involving genetically modified male mice were carried out in accordance with the Institutional Ethical Codex, Hungarian Act of Animal Care and Experimentation (1998, XXVIII, section 243/1998) and the European Union guidelines (directive 2010/63/EU), and with the approval of the Institutional Animal Care and Use Committee of the Institute of Experimental Medicine. All measures were taken to minimize potential stress or suffering during sacrifice and to reduce the number of animals to be used.

Human subjects: Ethic permissions were obtained from the Regional and Institutional Committee of Science and Research Ethics of Semmelweis University (SE-TUKEB 251/2016), in accordance with the Hungarian Law (1997 CLIV and 18/1998/XII.27. EÜM Decree/) and the World Medical Association Declaration of Helsinki. As explicitly declared in the Hungarian Law on Healthcare (1997. CLIV), tissue removal for either donation or research purposes can be done legally in Hungary, unless the deceased person banned the removal in advance. Therefore, collection and use of adult brain samples in this study did not require a priori informed consent of the deceased. The above cited legal article has been extended in 18/1998. (XII. 27. EÜM rendelet) decree of the Hungarian Ministry for Healthcare http://net.jogtar.hu/jr/gen/hjegy_doc.cgi?docid=99800018.EUM. Paragraph 6. speaks about requirements for "Removal of organ or tissue from a cadaver". Paragraph 8. states: Before removal the healthcare professional must check whether the personal documents or health care documentation of deceased person contains a "Declaration of Objection", i.e. explicit statement that he/she does not allow the removal of tissue or organs. In paragraph 8. (3): If such declaration does not exist, then the tissue or organs can be removed. The later Hungarian Law 1999. LXXI. also addresses this issue in the very same spirit: https://mkogy.jogtar.hu/jogszabaly?docid=99900071.TVFetal tissues were made available in accordance with French bylaws (Good Practice Concerning the Conservation, Transformation, and Transportation of Human Tissue to Be Used Therapeutically, published on December 29, 1998). The studies on human fetal tissue were approved by the French agency for biomedical research (Agence de la Biomédecine, Saint-Denis la Plaine, France, protocol n{degree sign}: PFS16-002). Non-pathological human fetuses were obtained at gestational week 11 from pregnancies terminated voluntarily after written informed consent of the parents (Gynaecology Department, Jeanne de Flandre Hospital, Lille, France).

Version history

  1. Received: February 19, 2021
  2. Accepted: June 14, 2021
  3. Accepted Manuscript published: June 15, 2021 (version 1)
  4. Version of Record published: June 30, 2021 (version 2)

Copyright

© 2021, Skrapits 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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  1. Katalin Skrapits
  2. Miklós Sárvári
  3. Imre Farkas
  4. Balázs Göcz
  5. Szabolcs Takács
  6. Éva Rumpler
  7. Viktória Váczi
  8. Csaba Vastagh
  9. Gergely Rácz
  10. András Matolcsy
  11. Norbert Solymosi
  12. Szilárd Póliska
  13. Blanka Tóth
  14. Ferenc Erdélyi
  15. Gábor Szabó
  16. Michael D Culler
  17. Cecile Allet
  18. Ludovica Cotellessa
  19. Vincent Prévot
  20. Paolo Giacobini
  21. Erik Hrabovszky
(2021)
The cryptic gonadotropin-releasing hormone neuronal system of human basal ganglia
eLife 10:e67714.
https://doi.org/10.7554/eLife.67714

Share this article

https://doi.org/10.7554/eLife.67714

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