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Upper airway patency is governed by genioglossal nerve activity that originates from the hypoglossal motor nucleus. Mice with targeted deletion of the gene\n                    <jats:italic>Hmox2,<\/jats:italic>\n                    encoding the carbon monoxide (CO) producing enzyme, heme oxygenase-2 (HO-2), exhibit OSA, yet the contribution of central HO-2 dysregulation to the phenomenon is unknown. Using the rhythmic brainstem slice preparation that contains the preB\u00f6tzinger complex (preB\u00f6tC) and the hypoglossal nucleus, we tested the hypothesis that central HO-2 dysregulation weakens hypoglossal motoneuron output. Disrupting HO-2 activity increased the occurrence of subnetwork activity from the preB\u00f6tC, which was associated with an increased irregularity of rhythmogenesis. These phenomena were also associated with the intermittent inability of the preB\u00f6tC rhythm to drive output from the hypoglossal nucleus (i.e. transmission failures), and a reduction in the input-output relationship between the preB\u00f6tC and the motor nucleus. HO-2 dysregulation reduced excitatory synaptic currents and intrinsic excitability in inspiratory hypoglossal neurons. Inhibiting activity of the CO-regulated H\n                    <jats:sub>2<\/jats:sub>\n                    S producing enzyme, cystathionine-\u03b3-lyase (CSE), reduced transmission failures in HO-2 null brainstem slices, which also normalized excitatory synaptic currents and intrinsic excitability of hypoglossal motoneurons. These findings demonstrate a hitherto uncharacterized modulation of hypoglossal activity through mutual interaction of HO-2\/CO and CSE\/H\n                    <jats:sub>2<\/jats:sub>\n                    S, and support the potential importance of centrally derived gasotransmitter activity in regulating upper airway control.\n                  <\/jats:p>","DOI":"10.7554\/elife.81978","type":"journal-article","created":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T08:15:25Z","timestamp":1674116125000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.81978","source":"Crossref","is-referenced-by-count":8,"title":["Gasotransmitter modulation of hypoglossal motoneuron activity"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1282-2290","authenticated-orcid":true,"given":"Brigitte M","family":"Browe","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for 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