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.
Reviewing Editor
- Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States
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.
Version history
- Received: October 9, 2017
- Accepted: October 29, 2017
- Accepted Manuscript published: October 31, 2017 (version 1)
- 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.
Metrics
-
- 1,352
- views
-
- 248
- downloads
-
- 25
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Neuroscience
Cortical folding is an important feature of primate brains that plays a crucial role in various cognitive and behavioral processes. Extensive research has revealed both similarities and differences in folding morphology and brain function among primates including macaque and human. The folding morphology is the basis of brain function, making cross-species studies on folding morphology important for understanding brain function and species evolution. However, prior studies on cross-species folding morphology mainly focused on partial regions of the cortex instead of the entire brain. Previously, our research defined a whole-brain landmark based on folding morphology: the gyral peak. It was found to exist stably across individuals and ages in both human and macaque brains. Shared and unique gyral peaks in human and macaque are identified in this study, and their similarities and differences in spatial distribution, anatomical morphology, and functional connectivity were also dicussed.
-
- Neuroscience
Complex skills like speech and dance are composed of ordered sequences of simpler elements, but the neuronal basis for the syntactic ordering of actions is poorly understood. Birdsong is a learned vocal behavior composed of syntactically ordered syllables, controlled in part by the songbird premotor nucleus HVC (proper name). Here, we test whether one of HVC’s recurrent inputs, mMAN (medial magnocellular nucleus of the anterior nidopallium), contributes to sequencing in adult male Bengalese finches (Lonchura striata domestica). Bengalese finch song includes several patterns: (1) chunks, comprising stereotyped syllable sequences; (2) branch points, where a given syllable can be followed probabilistically by multiple syllables; and (3) repeat phrases, where individual syllables are repeated variable numbers of times. We found that following bilateral lesions of mMAN, acoustic structure of syllables remained largely intact, but sequencing became more variable, as evidenced by ‘breaks’ in previously stereotyped chunks, increased uncertainty at branch points, and increased variability in repeat numbers. Our results show that mMAN contributes to the variable sequencing of vocal elements in Bengalese finch song and demonstrate the influence of recurrent projections to HVC. Furthermore, they highlight the utility of species with complex syntax in investigating neuronal control of ordered sequences.
