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

Medientyp: E-Artikel
Titel: Necdin shapes serotonergic development and SERT activity modulating breathing in a mouse model for Prader-Willi syndrome
Beteiligte: Matarazzo, Valéry; Caccialupi, Laura; Schaller, Fabienne; Shvarev, Yuri; Kourdougli, Nazim; Bertoni, Alessandra; Menuet, Clément; Voituron, Nicolas; Deneris, Evan; Gaspar, Patricia; Bezin, Laurent; Durbec, Pascale; Hilaire, Gérard; Muscatelli, Françoise
Erschienen: eLife Sciences Publications, Ltd, 2017
Erschienen in: eLife
Sprache: Englisch
DOI: 10.7554/elife.32640
ISSN: 2050-084X
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Beschreibung: <jats:p>Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder that presents with hypotonia and respiratory distress in neonates. The <jats:italic>Necdin</jats:italic>-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 <jats:italic>Necdin</jats:italic> 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 <jats:italic>Necdin</jats:italic>-KO pups, the genetic deletion of <jats:italic>Slc6a4</jats:italic> 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 <jats:italic>Necdin-</jats:italic>KO pups, and that fluoxetine may offer therapeutic benefits to PWS patients with respiratory complications.</jats:p>
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