Necdin shapes serotonergic development and SERT activity modulating breathing in a mouse model for Prader-Willi Syndrome
- Institut de Neurobiologie de la Méditerranée, France
- Karolinska Institutet, Sweden
- UFR STAPS, Université Paris 13, France
- Case Western Reserve University, United States
- INSERM, U839, Institut du Fer à Moulin, France
- Lyon Neuroscience Research Center, France
- 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
Françoise Muscatelli
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.
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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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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