Necdin Shapes Serotonergic Development and SERT Activity Modulating Breathing in a Mouse Model for Prader-Willi Syndrome

Overview

Journal Elife

Specialty Biology

Date 2017 Nov 1

PMID 29087295

Citations 17

Authors

Valery Matarazzo

Laura Caccialupi

Fabienne Schaller

Yuri Shvarev

Nazim Kourdougli

Alessandra Bertoni

Clement Menuet

Nicolas Voituron

Evan Deneris

Patricia Gaspar

Laurent Bezin

Pascale Durbec

Gerard Hilaire

Francoise Muscatelli

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Hormonal Imbalances in Prader-Willi and Schaaf-Yang Syndromes Imply the Evolution of Specific Regulation of Hypothalamic Neuroendocrine Function in Mammals.

Sanchez M, Bayat T, Gee R, Fon Tacer K Int J Mol Sci. 2023; 24(17).

PMID: 37685915 PMC: 10487939. DOI: 10.3390/ijms241713109.

CNTNAP2 intracellular domain (CICD) generated by γ-secretase cleavage improves autism-related behaviors.

Zhang J, Cai F, Lu R, Xing X, Xu L, Wu K Signal Transduct Target Ther. 2023; 8(1):219.

PMID: 37271769 PMC: 10239753. DOI: 10.1038/s41392-023-01431-6.

The integrated brain network that controls respiration.

Krohn F, Novello M, van der Giessen R, De Zeeuw C, Pel J, Bosman L Elife. 2023; 12.

PMID: 36884287 PMC: 9995121. DOI: 10.7554/eLife.83654.

Next Steps in Prader-Willi Syndrome Research: On the Relationship between Genotype and Phenotype.

Whittington J, Holland A Int J Mol Sci. 2022; 23(20).

PMID: 36292940 PMC: 9603642. DOI: 10.3390/ijms232012089.

Necdin: A purposive integrator of molecular interaction networks for mammalian neuron vitality.

Yoshikawa K Genes Cells. 2021; 26(9):641-683.

PMID: 34338396 PMC: 9290590. DOI: 10.1111/gtc.12884.

References

Berner J, Shvarev Y, Zimmer A, Wickstrom R . Hypoxic ventilatory response in Tac1-/- neonatal mice following exposure to opioids. J Appl Physiol (1985). 2012; 113(11):1718-26. DOI: 10.1152/japplphysiol.00188.2012. View

Zanella S, Watrin F, Mebarek S, Marly F, Roussel M, Gire C . Necdin plays a role in the serotonergic modulation of the mouse respiratory network: implication for Prader-Willi syndrome. J Neurosci. 2008; 28(7):1745-55. PMC: 6671529. DOI: 10.1523/JNEUROSCI.4334-07.2008. View

Gozal D, Arens R, Omlin K, Ward S, Keens T . Absent peripheral chemosensitivity in Prader-Willi syndrome. J Appl Physiol (1985). 1994; 77(5):2231-6. DOI: 10.1152/jappl.1994.77.5.2231. View

Pagliardini S, Rent J, Wevrick R, Greer J . Neurodevelopmental abnormalities in the brainstem of prenatal mice lacking the Prader-Willi syndrome gene Necdin. Adv Exp Med Biol. 2007; 605:139-43. DOI: 10.1007/978-0-387-73693-8_24. View

Cohen M, Hamilton J, Narang I . Clinically important age-related differences in sleep related disordered breathing in infants and children with Prader-Willi Syndrome. PLoS One. 2014; 9(6):e101012. PMC: 4076199. DOI: 10.1371/journal.pone.0101012. View

Schluter B, Buschatz D, Trowitzsch E, Aksu F, Andler W . Respiratory control in children with Prader-Willi syndrome. Eur J Pediatr. 1997; 156(1):65-8. DOI: 10.1007/s004310050555. View

Aebischer J, Sturny R, Andrieu D, Rieusset A, Schaller F, Geib S . Necdin protects embryonic motoneurons from programmed cell death. PLoS One. 2011; 6(9):e23764. PMC: 3166279. DOI: 10.1371/journal.pone.0023764. View

Pavone M, Caldarelli V, Khirani S, Colella M, Ramirez A, Aubertin G . Sleep disordered breathing in patients with Prader-Willi syndrome: A multicenter study. Pediatr Pulmonol. 2015; 50(12):1354-9. DOI: 10.1002/ppul.23177. View

Kinney H, Broadbelt K, Haynes R, Rognum I, Paterson D . The serotonergic anatomy of the developing human medulla oblongata: implications for pediatric disorders of homeostasis. J Chem Neuroanat. 2011; 41(4):182-99. PMC: 3134154. DOI: 10.1016/j.jchemneu.2011.05.004. View

10.

Kachidian P, Poulat P, Marlier L, Privat A . Immunohistochemical evidence for the coexistence of substance P, thyrotropin-releasing hormone, GABA, methionine-enkephalin, and leucin-enkephalin in the serotonergic neurons of the caudal raphe nuclei: a dual labeling in the rat. J Neurosci Res. 1991; 30(3):521-30. DOI: 10.1002/jnr.490300309. View

11.

Mouri A, Sasaki A, Watanabe K, Sogawa C, Kitayama S, Mamiya T . MAGE-D1 regulates expression of depression-like behavior through serotonin transporter ubiquitylation. J Neurosci. 2012; 32(13):4562-80. PMC: 6622051. DOI: 10.1523/JNEUROSCI.6458-11.2012. View

12.

Lau T, Proissl V, Ziegler J, Schloss P . Visualization of neurotransmitter uptake and release in serotonergic neurons. J Neurosci Methods. 2014; 241:10-7. DOI: 10.1016/j.jneumeth.2014.12.009. View

13.

Tennese A, Gee C, Wevrick R . Loss of the Prader-Willi syndrome protein necdin causes defective migration, axonal outgrowth, and survival of embryonic sympathetic neurons. Dev Dyn. 2008; 237(7):1935-43. DOI: 10.1002/dvdy.21615. View

14.

Kuwako K, Hosokawa A, Nishimura I, Uetsuki T, Yamada M, Nada S . Disruption of the paternal necdin gene diminishes TrkA signaling for sensory neuron survival. J Neurosci. 2005; 25(30):7090-9. PMC: 6724840. DOI: 10.1523/JNEUROSCI.2083-05.2005. View

15.

Liu X, Wang Y, Zhang Y, Zhu W, Xu X, Niinobe M . Nogo-A inhibits necdin-accelerated neurite outgrowth by retaining necdin in the cytoplasm. Mol Cell Neurosci. 2009; 41(1):51-61. DOI: 10.1016/j.mcn.2009.01.009. View

16.

Hilaire G, Voituron N, Menuet C, Ichiyama R, Subramanian H, Dutschmann M . The role of serotonin in respiratory function and dysfunction. Respir Physiol Neurobiol. 2010; 174(1-2):76-88. PMC: 2993113. DOI: 10.1016/j.resp.2010.08.017. View

17.

Voituron N, Shvarev Y, Menuet C, Bevengut M, Fasano C, Vigneault E . Fluoxetine treatment abolishes the in vitro respiratory response to acidosis in neonatal mice. PLoS One. 2010; 5(10):e13644. PMC: 2964329. DOI: 10.1371/journal.pone.0013644. View

18.

Festen D, de Weerd A, van den Bossche R, Joosten K, Hoeve H, Hokken-Koelega A . Sleep-related breathing disorders in prepubertal children with Prader-Willi syndrome and effects of growth hormone treatment. J Clin Endocrinol Metab. 2006; 91(12):4911-5. DOI: 10.1210/jc.2006-0765. View

19.

Takazaki R, Nishimura I, Yoshikawa K . Necdin is required for terminal differentiation and survival of primary dorsal root ganglion neurons. Exp Cell Res. 2002; 277(2):220-32. DOI: 10.1006/excr.2002.5558. View

20.

Muscatelli F, Abrous D, MASSACRIER A, Boccaccio I, Le Moal M, Cau P . Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome. Hum Mol Genet. 2000; 9(20):3101-10. DOI: 10.1093/hmg/9.20.3101. View