Necdin shapes serotonergic development and SERT activity modulating breathing in a mouse model for Prader-Willi Syndrome

  1. Valéry Matarazzo  Is a corresponding author
  2. Laura Caccialupi
  3. Fabienne Schaller
  4. Yuri Shvarev
  5. Nazim Kourdougli
  6. Alessandra Bertoni
  7. Clément Menuet
  8. Nicolas Voituron
  9. Evan Deneris
  10. Patricia Gaspar
  11. Laurent Bezin
  12. Pascale Durbec
  13. Gérard Hilaire
  14. Françoise Muscatelli  Is a corresponding author
  1. Institut de Neurobiologie de la Méditerranée, France
  2. Karolinska Institutet, Sweden
  3. UFR STAPS, Université Paris 13, France
  4. Case Western Reserve University, United States
  5. INSERM, U839, Institut du Fer à Moulin, France
  6. Lyon Neuroscience Research Center, France
  7. Aix Marseille University CNRS, France

Abstract

Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder that presents with hypotonia and respiratory distress in neonates. The Necdin-deficient mouse is the only model that reproduces the respiratory phenotype of PWS (central apnea and blunted response to respiratory challenges). Here, we report that Necdin deletion disturbs the migration of serotonin (5-HT) neuronal precursors, leading to altered global serotonergic neuroarchitecture and increased spontaneous firing of 5-HT neurons. We show an increased expression and activity of 5-HT Transporter (SERT/Slc6a4) in 5-HT neurons leading to an increase of 5-HT uptake. In Necdin-KO pups, the genetic deletion of Slc6a4 or treatment with Fluoxetine, a 5-HT reuptake inhibitor, restored normal breathing. Unexpectedly, Fluoxetine administration was associated with respiratory side effects in wild-type animals. Overall, our results demonstrate that an increase of SERT activity is sufficient to cause the apneas in Necdin-KO pups, and that Fluoxetine may offer therapeutic benefits to PWS patients with respiratory complications.

Article and author information

Author details

  1. Valéry Matarazzo

    INSERM U901, Institut de Neurobiologie de la Méditerranée, Marseille, France
    For correspondence
    valery.matarazzo@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0833-203X
  2. Laura Caccialupi

    INSERM U901, Institut de Neurobiologie de la Méditerranée, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Fabienne Schaller

    INSERM U901, Institut de Neurobiologie de la Méditerranée, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Yuri Shvarev

    Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6622-1453
  5. Nazim Kourdougli

    INSERM U901, Institut de Neurobiologie de la Méditerranée, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8725-792X
  6. Alessandra Bertoni

    INSERM U901, Institut de Neurobiologie de la Méditerranée, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Clément Menuet

    INSERM U901, Institut de Neurobiologie de la Méditerranée, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7419-6427
  8. Nicolas Voituron

    UFR STAPS, Université Paris 13, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2092-4900
  9. Evan Deneris

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Patricia Gaspar

    INSERM, U839, Institut du Fer à Moulin, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4217-5717
  11. Laurent Bezin

    CNRS, Lyon Neuroscience Research Center, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Pascale Durbec

    IBDM UMR7288, Aix Marseille University CNRS, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9660-1809
  13. Gérard Hilaire

    INSERM U901, Institut de Neurobiologie de la Méditerranée, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Françoise Muscatelli

    INSERM U901, Institut de Neurobiologie de la Méditerranée, Marseille, France
    For correspondence
    francoise.muscatelli@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4001-6528

Funding

Institut National de la Santé et de la Recherche Médicale

  • Valéry Matarazzo
  • Laura Caccialupi
  • Fabienne Schaller
  • Nazim Kourdougli
  • Alessandra Bertoni
  • Clément Menuet
  • Patricia Gaspar
  • Françoise Muscatelli

Centre National de la Recherche Scientifique

  • Laurent Bezin
  • Pascale Durbec
  • Gérard Hilaire
  • Françoise Muscatelli

Agence Nationale de la Recherche (PRAGEDER ANR14-CE13-0025-01)

  • Valéry Matarazzo
  • Fabienne Schaller
  • Yuri Shvarev
  • Clément Menuet
  • Nicolas Voituron
  • Gérard Hilaire
  • Françoise Muscatelli

Stiftelsen Frimurare Barnhuset i Stockholm

  • Yuri Shvarev

Kronprinsessan Lovisas Forening for Barnasjukvard

  • Yuri Shvarev

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

Ethics

Animal experimentation: Mice were handled and cared for in accordance with the Guide for the Care and Use of Laboratory Animals (N.R.C., 1996) and the European Communities Council Directive of September 22th 2010 (2010/63/EU, 74). Experimental protocols were approved by the Institutional Ethical Committee guidelines for animal research with the accreditation no. B13-055-19 from the French Ministry of Agriculture.

Reviewing Editor

  1. Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States

Publication history

  1. Received: October 9, 2017
  2. Accepted: October 29, 2017
  3. Accepted Manuscript published: October 31, 2017 (version 1)
  4. Version of Record published: December 1, 2017 (version 2)

Copyright

© 2017, Matarazzo 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. Valéry Matarazzo
  2. Laura Caccialupi
  3. Fabienne Schaller
  4. Yuri Shvarev
  5. Nazim Kourdougli
  6. Alessandra Bertoni
  7. Clément Menuet
  8. Nicolas Voituron
  9. Evan Deneris
  10. Patricia Gaspar
  11. Laurent Bezin
  12. Pascale Durbec
  13. Gérard Hilaire
  14. Françoise Muscatelli
(2017)
Necdin shapes serotonergic development and SERT activity modulating breathing in a mouse model for Prader-Willi Syndrome
eLife 6:e32640.
https://doi.org/10.7554/eLife.32640
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