title: Pharmacological, but not genetic, alteration of neural Epo modifies the CO2/H+central chemosensitivity in postnatal mice.
abstract: Cerebral erythropoietin (Epo) plays a crucial role for respiratory control in newborn rodents. We showed previously that soluble Epo receptor (sEpoR: an Epo antagonist) reduces basal ventilation and hypoxic hyperventilation at postnatal day 10 (P10) and in adult mice. However, at these ages (P10 and adulthood), Epo had no effect on central chemosensitivity. Nevertheless, it is known that the sensitivity to CO2/H+during the mammalian respiratory network maturation process is age-dependent. Accordingly, in this study we wanted to test the hypothesis that cerebral Epo is involved in the breathing stimulation induced by the activation of central CO2/H+chemoreceptors at earlier postnatal ages. To this end, en bloc brainstem-spinal cord preparations were obtained from P4 mice and the fictive breathing response to CO2-induced acidosis or metabolic acidosis was analyzed. This age (P4) was chosen because previous research from our laboratory showed that Epo altered (in a dose- and time-dependent manner) the fictive ventilation elicited in brainstem-spinal cord preparations. Moreover, as it was observed that peripheral chemoreceptors determined the respiratory sensitivity of central chemoreceptors to CO2, the use of this technique restricts our observations to central modulation. Our results did not show differences between preparations from control and transgenic animals (Tg21: overexpressing cerebral Epo; Epo-TAgh: cerebral Epo deficient mice). However, when Tg21 brainstem preparations were incubated for 1h with sEpoR, or with inhibitors of ERK/Akt (thus blocking the activation of the Epo molecular pathway), the fictive breathing response to CO2-induced acidosis was blunted. Our data suggest that variation of the Epo/sEpoR ratio is central to breathing modulation during CO2challenges, and calls attention to clinical perspectives based on the use of Epo drugs at birth in hypoventilation cases.
authors.affiliation: Université Laval, Faculté de Médecine, Centre de Recherche Institut universitaire de cardiologie et de pneumologie de Québec, Département de Pédiatrie, Québec, QC, Canada; LEHNA, UMR CNRS 5023, Ecologie des Hydrosystèmes Naturels et Anthropisés, Université de Lyon, Université Lyon 1, ENTPE, 6 rue Raphael Dubois, 69622 Villeurbanne, France.
authors.forename: Sofien
authors.initials: S
authors.lastname: Laouafa
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Laboratoire "Hypoxie et poumons", EA 2363, 93017 Bobigny, France; Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S1158 Neurophysiologie Respiratoire Expérimentale et Clinique, F-75013, Paris, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Perrin-Terrin
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Laboratoire "Hypoxie et poumons", EA 2363, 93017 Bobigny, France.
authors.forename: Florine
authors.initials: F
authors.lastname: Jeton
authors.affiliation: Université Laval, Faculté de Médecine, Centre de Recherche Institut universitaire de cardiologie et de pneumologie de Québec, Département de Pédiatrie, Québec, QC, Canada; Molecular biology and Biotechnology Institute, Universidad Mayor de San Andres, La Paz, Bolivia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Elliot-Portal
authors.affiliation: Université Laval, Faculté de Médecine, Centre de Recherche Institut universitaire de cardiologie et de pneumologie de Québec, Département de Pédiatrie, Québec, QC, Canada.
authors.forename: Rose
authors.initials: R
authors.lastname: Tam
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S1158 Neurophysiologie Respiratoire Expérimentale et Clinique, F-75013, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Bodineau
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Laboratoire "Hypoxie et poumons", EA 2363, 93017 Bobigny, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Voituron
authors.affiliation: Université Laval, Faculté de Médecine, Centre de Recherche Institut universitaire de cardiologie et de pneumologie de Québec, Département de Pédiatrie, Québec, QC, Canada; Molecular biology and Biotechnology Institute, Universidad Mayor de San Andres, La Paz, Bolivia. Electronic address: jorge.soliz@criucpq.ulaval.ca.
authors.forename: Jorge
authors.initials: J
authors.lastname: Soliz
mesh_terms: D000138:Acidosis / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism*; D002245:Carbon Dioxide / Q000378:metabolism*; D004921:Erythropoietin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011522:Protons; D017467:Receptors, Erythropoietin / Q000037:antagonists & inhibitors / Q000378:metabolism; D012119:Respiration / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D011522:Protons; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D002245:Carbon Dioxide; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Central chemosensitivity; ERK/Akt; Erythropoietin; Hypercapnia; Newborn mice; Respiration; Soluble erythropoietin receptor