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Mafa-dependent GABAergic activity promotes mouse neonatal apneas

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Item Type:Article
Title:Mafa-dependent GABAergic activity promotes mouse neonatal apneas
Creators Name:Lecoin, L. and Dempsey, B. and Garancher, A. and Bourane, S. and Ruffault, P.L. and Morin-Surun, M.P. and Rocques, N. and Goulding, M. and Eychène, A. and Pouponnot, C. and Fortin, G. and Champagnat, J.
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 (Mafa(4A)) 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.
Keywords:Apnea, Genetic Promoter Regions, Large Maf Transcription Factors, Motor Neurons, Phosphorylation, Animals, Mice
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:3284
Date:7 June 2022
Official Publication:https://doi.org/10.1038/s41467-022-30825-3
PubMed:View item in PubMed

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