Matarazzo V - Caccialupi L - Schaller F - Shvarev Y - Kourdougli N - Bertoni A - Menuet C - Voituron N - Deneris E - Gaspar P - Bezin L - Durbec P - Hilaire G - Muscatelli F




Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder that presents with hypotonia and respiratory distress in neonates. The -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 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 -KO pups, the genetic deletion of 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 KO pups, and that fluoxetine may offer therapeutic benefits to PWS patients with respiratory complications.

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