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.
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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
Further reading
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Probing memory of a complex visual image within a few hundred milliseconds after its disappearance reveals significantly greater fidelity of recall than if the probe is delayed by as little as a second. Classically interpreted, the former taps into a detailed but rapidly decaying visual sensory or ‘iconic’ memory (IM), while the latter relies on capacity-limited but comparatively stable visual working memory (VWM). While iconic decay and VWM capacity have been extensively studied independently, currently no single framework quantitatively accounts for the dynamics of memory fidelity over these time scales. Here, we extend a stationary neural population model of VWM with a temporal dimension, incorporating rapid sensory-driven accumulation of activity encoding each visual feature in memory, and a slower accumulation of internal error that causes memorized features to randomly drift over time. Instead of facilitating read-out from an independent sensory store, an early cue benefits recall by lifting the effective limit on VWM signal strength imposed when multiple items compete for representation, allowing memory for the cued item to be supplemented with information from the decaying sensory trace. Empirical measurements of human recall dynamics validate these predictions while excluding alternative model architectures. A key conclusion is that differences in capacity classically thought to distinguish IM and VWM are in fact contingent upon a single resource-limited WM store.
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Our ability to recall details from a remembered image depends on a single mechanism that is engaged from the very moment the image disappears from view.
