Mafa-dependent GABAergic activity promotes mouse neonatal apneas

Laure Lecoin (), Bowen Dempsey, Alexandra Garancher, Steeve Bourane, Pierre-Louis Ruffault, Marie-Pierre Morin-Surun, Nathalie Rocques, Martyn Goulding, Alain Eychène, Celio Pouponnot (), Gilles Fortin () and Jean Champagnat
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Laure Lecoin: Institut Curie CNRS UMR 3347, Inserm U1021, UPSaclay, bat 110 Centre Universitaire
Bowen Dempsey: UMR 9194 CNRS Neuro-PSI, Institut de Neurobiologie Alfred Fessard, 1 avenue de la terrasse
Alexandra Garancher: Institut Curie CNRS UMR 3347, Inserm U1021, UPSaclay, bat 110 Centre Universitaire
Steeve Bourane: The Salk Institute for Biological Studies
Pierre-Louis Ruffault: Max Delbrück Center for Molecular Medicine
Marie-Pierre Morin-Surun: UMR 9194 CNRS Neuro-PSI, Institut de Neurobiologie Alfred Fessard, 1 avenue de la terrasse
Nathalie Rocques: Institut Curie CNRS UMR 3347, Inserm U1021, UPSaclay, bat 110 Centre Universitaire
Martyn Goulding: The Salk Institute for Biological Studies
Alain Eychène: Institut Curie CNRS UMR 3347, Inserm U1021, UPSaclay, bat 110 Centre Universitaire
Celio Pouponnot: Institut Curie CNRS UMR 3347, Inserm U1021, UPSaclay, bat 110 Centre Universitaire
Gilles Fortin: UMR 9194 CNRS Neuro-PSI, Institut de Neurobiologie Alfred Fessard, 1 avenue de la terrasse
Jean Champagnat: UMR 9194 CNRS Neuro-PSI, Institut de Neurobiologie Alfred Fessard, 1 avenue de la terrasse

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract While apneas are associated with multiple pathological and fatal conditions, the underlying molecular mechanisms remain elusive. We report that a mutated form of the transcription factor Mafa (Mafa4A) that prevents phosphorylation of the Mafa protein leads to an abnormally high incidence of breath holding apneas and death in newborn Mafa4A/4A mutant mice. This apneic breathing is phenocopied by restricting the mutation to central GABAergic inhibitory neurons and by activation of inhibitory Mafa neurons while reversed by inhibiting GABAergic transmission centrally. We find that Mafa activates the Gad2 promoter in vitro and that this activation is enhanced by the mutation that likely results in increased inhibitory drives onto target neurons. We also find that Mafa inhibitory neurons are absent from respiratory, sensory (primary and secondary) and pontine structures but are present in the vicinity of the hypoglossal motor nucleus including premotor neurons that innervate the geniohyoid muscle, to control upper airway patency. Altogether, our data reveal a role for Mafa phosphorylation in regulation of GABAergic drives and suggest a mechanism whereby reduced premotor drives to upper airway muscles may cause apneic breathing at birth.

Date: 2022
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DOI: 10.1038/s41467-022-30825-3

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