Necdin shapes serotonergic development and SERT activity modulating breathing in a mouse model for Prader-Willi syndrome - Université Pierre et Marie Curie Accéder directement au contenu
Article Dans Une Revue eLife Année : 2017

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

Yuri Shvarev
Patricia Gaspar

Résumé

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.

Dates et versions

hal-01690409 , version 1 (23-01-2018)

Identifiants

Citer

Valéry Matarazzo, Laura Caccialupi, Fabienne Schaller, Yuri Shvarev, Nazim Kourdougli, et al.. Necdin shapes serotonergic development and SERT activity modulating breathing in a mouse model for Prader-Willi syndrome. eLife, 2017, 6, ⟨10.7554/eLife.32640⟩. ⟨hal-01690409⟩
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