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Exposure to retinoic acid at the onset of hindbrain segmentation induces episodic breathing in mice

Authors

  • Laura Guimarães,

    1. Neurobiologie Génétique et Intégrative, UPR 2216, CNRS, Gif-sur-Yvette, France
    2. Dept. Estudos de Populações, Instituto Ciências Biomédicas Abel Salazar, Porto, Portugal
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    • *

      Present address: CIIMAR, Centro Interdisciplinar de Investigação Marinha e Ambiental, Laboratório de Ecotoxicologia, Rua dos Bragas 177, 4050-123 Porto, Portugal

    • L.G., E.D.-d.-T. and F.C. contributed equally to this work.

  • Eduardo Domínguez-del-Toro,

    1. Neurobiologie Génétique et Intégrative, UPR 2216, CNRS, Gif-sur-Yvette, France
    2. División de Neurociencias, Universidad Pablo de Olavide, Ctra. de Utrera, Km 1, Sevilla 41013, Spain
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    • L.G., E.D.-d.-T. and F.C. contributed equally to this work.

  • Fabrice Chatonnet,

    1. Neurobiologie Génétique et Intégrative, UPR 2216, CNRS, Gif-sur-Yvette, France
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    • Present address: Institut de Génomique Fonctionelle de Lyon, UMR5242 CNRS/INRA/INSERM/École Normale Supérieure de Lyon, 46 allée d'Italie, 69364 Lyon Cedex 07, France

    • L.G., E.D.-d.-T. and F.C. contributed equally to this work.

  • Ludovic Wrobel,

    1. Neurobiologie Génétique et Intégrative, UPR 2216, CNRS, Gif-sur-Yvette, France
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  • Cristina Pujades,

    1. Developmental Biology Group, Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
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  • Luís S. Monteiro,

    1. Dept. Estudos de Populações, Instituto Ciências Biomédicas Abel Salazar, Porto, Portugal
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  • Jean Champagnat

    1. Neurobiologie Génétique et Intégrative, UPR 2216, CNRS, Gif-sur-Yvette, France
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Dr Eduardo Domínguez del Toro, 3División de Neurociencias, as above.
E-mail: edomtor@upo.es

Abstract

Hyperpnoeic episodic breathing (HEB), a cyclic waxing and waning of breathing, has been widely reported in pre-term neonates, patients with Joubert syndrome and adults (Cheyne-Stokes respiration) with congestive heart failure and brainstem infarction. We now provide a developmental mouse model of neonatal HEB. We used retinoic acid (RA) (0.5–10 mg/kg of maternal weight) to alter embryonic development of the respiratory neuronal network at the onset of hindbrain segmentation (7.5 days post-coitum). HEB was observed in vivo after RA treatment during post-natal days 1–7 but not in control animals. HEB persisted after reduction of the chemoafferent input by hypocapnic hyperoxia (100% O2). A large increase and decrease of the rhythm resembling an HEB episode was induced in vitro by stimulating the parafacial respiratory oscillator in treated but not in control neonates. Post-natal localization of the superior cerebellar peduncle and adjacent dorsal tegmentum was found to be abnormal in the pons of RA-treated juvenile mice. Thus, early developmental specifications in the rostral hindbrain are required for the development of neurones that stabilize the function of the respiratory rhythm generator, thereby preventing HEB during post-natal maturation.

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