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.
Highlights
Respiration is a complex function controlled in large part by raphe serotonergic (5-HT) neurons (Teran et al, 2014)
Central 5-HT depletion induces severe apneas during the early postnatal period (Barrett et al, 2016; Trowbridge et al, 2011) and serotonopathy is implicated in the genesis of breathing disorders in human pathologies including neurodevelopmental diseases such as Sudden Infant Death Syndrome (Duncan et al, 2010; Hilaire et al, 2010; Kinney et al, 2011; Paterson et al, 2009), Rett syndrome (Abdala et al, 2010; Toward et al, 2013) and Prader-Willi Syndrome (PWS) (Zanella et al, 2008)
We assessed whether Necdin deficiency could induce alterations of 5-HT neuronal development
Summary
Respiration is a complex function controlled in large part by raphe serotonergic (5-HT) neurons (Teran et al, 2014). Its associated respiratory disturbances (Miller and Wagner, 2013; Nixon and Brouillette, 2002; Tan and Urquhart, 2017) are highly disruptive to the daily life of patients and represent the most common cause of death (73% of infants and 26% of adults) (Butler et al, 2017).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
