{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:28:38Z","timestamp":1790191718427,"version":"4.1.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,16]],"date-time":"2022-02-16T00:00:00Z","timestamp":1644969600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Prenatal hypoxia is a recognised risk factor for neurodevelopmental disorders associated with both membrane proteins involved in neuron homeostasis, e.g., chloride (Cl<jats:sup>\u2013<\/jats:sup>) cotransporters, and alterations in brain neurotransmitter systems, e.g., catecholamines, dopamine, and GABA. Our study aimed to determine whether prenatal hypoxia alters central respiratory drive by disrupting the development of Cl<jats:sup>\u2013<\/jats:sup> cotransporters KCC2 and NKCC1. Cl<jats:sup>\u2013<\/jats:sup> homeostasis seems critical for the strength and efficiency of inhibition mediated by GABA<jats:sub>A<\/jats:sub> and glycine receptors within the respiratory network, and we searched for alterations of GABAergic and glycinergic respiratory influences after prenatal hypoxia. We measured fictive breathing from brainstem in <jats:italic>ex vivo<\/jats:italic> preparations during pharmacological blockade of KCC2 and NKCC1 Cl<jats:sup>\u2013<\/jats:sup> cotransporters, GABA<jats:sub>A<\/jats:sub>, and glycine receptors. We also evaluated the membrane expression of Cl<jats:sup>\u2013<\/jats:sup> cotransporters in the brainstem by Western blot and the expression of Cl<jats:sup>\u2013<\/jats:sup> cotransporter regulators brain-derived neurotrophic factor (BDNF) and calpain. First, pharmacological experiments showed that prenatal hypoxia altered the regulation of fictive breathing by NKCC1 and KCC2 Cl<jats:sup>\u2013<\/jats:sup> cotransporters, GABA\/GABA<jats:sub>A<\/jats:sub>, and glycin. NKCC1 inhibition decreased fictive breathing at birth in control mice while it decreased at 4 days after birth in pups exposed to prenatal hypoxia. On the other hand, inhibition of KCC2 decreased fictive breathing 4 days after birth in control mice without any change in prenatal hypoxia pups. The GABAergic system appeared to be more effective in prenatal hypoxic pups whereas the glycinergic system increased its effectiveness later. Second, we observed a decrease in the expression of the Cl<jats:sup>\u2013<\/jats:sup> cotransporter KCC2, and a decrease with age in NKCC1, as well as an increase in the expression of BDNF and calpain after prenatal hypoxia exposure. Altogether, our data support the idea that prenatal hypoxia alters the functioning of GABA<jats:sub>A<\/jats:sub> and glycinergic systems in the respiratory network by disrupting maturation of Cl<jats:sup>\u2013<\/jats:sup> homeostasis, thereby contributing to long-term effects by disrupting ventilation.<\/jats:p>","DOI":"10.3389\/fphys.2022.786714","type":"journal-article","created":{"date-parts":[[2022,2,16]],"date-time":"2022-02-16T07:17:52Z","timestamp":1644995872000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Prenatal Hypoxia Induces Cl\u2013 Cotransporters KCC2 and NKCC1 Developmental Abnormality and Disturbs the Influence of GABAA and Glycine Receptors on Fictive Breathing in a Newborn Rat"],"prefix":"10.3389","volume":"13","author":[{"given":"C\u00e9line","family":"Caravagna","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Casciato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques-Olivier","family":"Coq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Liabeuf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"Brocard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Peyronnet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Bodineau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Cayetanot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1038\/nature18944","article-title":"A novel excitatory network for the control of breathing.","volume":"536","author":"Anderson","year":"2016","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/0140-6736(93)91224-A","article-title":"Fetal nutrition and cardiovascular disease in adult life.","volume":"341","author":"Barker","year":"1993","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1750-3639.2004.tb00492.x","article-title":"Gestational hypoxia induces white matter damage in neonatal rats: a new model of periventricular leukomalacia.","volume":"14","author":"Baud","year":"2004","journal-title":"Brain Pathol."},{"key":"B4","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.neuron.2009.03.003","article-title":"Cation-chloride cotransporters and neuronal function.","volume":"61","author":"Blaesse","year":"2009","journal-title":"Neuron"},{"key":"B5","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/s0006-8993(96)01273-5","article-title":"Identification of brainstem neurons responding to hypoxia in fetal and newborn sheep.","volume":"748","author":"Breen","year":"1997","journal-title":"Brain Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1177\/0885066604269663","article-title":"Current concepts in intrauterine growth restriction.","volume":"19","author":"Brodsky","year":"2004","journal-title":"J. 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