Necdin plays a role in the serotonergic modulation of the mouse respiratory network: implication for Prader-Willi syndrome.
Prader-Willi syndrome is a neurogenetic disease resulting from the absence of paternal expression of several imprinted genes, including NECDIN. Prader-Willi children and adults have severe breathing defects with irregular rhythm, frequent sleep apneas, and blunted respiratory regulations. For the first time, we show that Prader-Willi infants have sleep apneas already present at birth. In parallel, in wild-type and Necdin-deficient mice, we studied the respiratory system with in vivo plethysmography, in vitro electrophysiology, and pharmacology. Because serotonin is known to contribute to CNS development and to affect maturation and function of the brainstem respiratory network, we also investigated the serotonergic system with HPLC, immunohistochemistry, Rabies virus tracing approaches, and primary culture experiments. We report first that Necdin-deficiency in mice induces central respiratory deficits reminiscent of Prader-Willi syndrome (irregular rhythm, frequent apneas, and blunted respiratory regulations), second that Necdin is expressed by medullary serotonergic neurons, and third that Necdin deficiency alters the serotonergic metabolism, the morphology of serotonin vesicles in medullary serotonergic neurons but not the number of these cells. We also show that Necdin deficiency in neonatal mice alters the serotonergic modulation of the respiratory rhythm generator. Thus, we propose that the lack of Necdin expression induces perinatal serotonergic alterations that affect the maturation and function of the respiratory network, inducing breathing deficits in mice and probably in Prader-Willi patients.
Zanella
Sébastien
S
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6231, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Faculté Saint Jérôme, Case 362, 13397 Marseille Cedex 20, France.
Watrin
Françoise
F
Mebarek
Saïda
S
Marly
Fabienne
F
Roussel
Michel
M
Gire
Catherine
C
Diene
Gwenaëlle
G
Tauber
Maïté
M
Muscatelli
Françoise
F
Hilaire
Gérard
G
D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002675:Child, Preschool; D004195:Disease Models, Animal; D006801:Humans; D007223:Infant; D008526:Medulla Oblongata / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D011218:Prader-Willi Syndrome / Q000235:genetics* / Q000378:metabolism*; D012119:Respiration / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism*; D012891:Sleep Apnea Syndromes / Q000503:physiopathology*; D013116:Spinal Cord / Q000378:metabolism
D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C069766:necdin; D012701:Serotonin