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The Journal of Neuroscience, February 13, 2008, 28(7):1745-1755; doi:10.1523/JNEUROSCI.4334-07.2008

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Neurobiology of Disease
Necdin Plays a Role in the Serotonergic Modulation of the Mouse Respiratory Network: Implication for Prader-Willi Syndrome

Sébastien Zanella,¹ Françoise Watrin,² Saïda Mebarek,^1,2 Fabienne Marly,² Michel Roussel,³ Catherine Gire,⁴ Gwenaëlle Diene,⁵ Maïté Tauber,⁵ Françoise Muscatelli,^2 * and Gérard Hilaire^1 *

¹Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6231, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Equipe Maturation, Plasticité, Physiologie Pathologie de la Respiration, Faculté Saint Jérôme, Case 362, 13397 Marseille Cedex 20, France, ² Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6216, Institut de Biologie du Développement de Marseille, Luminy, 13288 Marseille Cedex 9, France, ³Service de Neurophysiologie Clinique and ⁴Service de Pédiatrie, Centre Hostitalier Universitaire Nord-Chemin des Bourrely, 13015 Marseille, France, and ⁵Hôpital des Enfants, 734 31026 Toulouse Cedex 3, France

Correspondence should be addressed to Gérard Hilaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6231, Equipe Maturation, Plasticité, Physilogie et Pathologie de la Respiration, Faculté Saint Jérôme, Case 362, 13397 Marseille Cedex 20, France. Email: gerard.hilaire{at}univ-cezanne.fr

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.

Key words: Prader-Willi syndrome; Necdin; respiratory system; serotonin; infants; mice

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Received March 30, 2007; revised Dec. 20, 2007; accepted Dec. 24, 2007.

Correspondence should be addressed to Gérard Hilaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6231, Equipe Maturation, Plasticité, Physilogie et Pathologie de la Respiration, Faculté Saint Jérôme, Case 362, 13397 Marseille Cedex 20, France. Email: gerard.hilaire{at}univ-cezanne.fr

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