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PTHS is caused by functional haploinsufficiency of the gene encoding transcription factor 4 (<jats:italic>Tcf4<\/jats:italic>). Despite the severity of this disease, mechanisms contributing to PTHS behavioral abnormalities are not well understood. Here, we show that a <jats:italic>Tcf4<\/jats:italic> truncation (<jats:italic>Tcf4<\/jats:italic><jats:sup>tr\/+<\/jats:sup>) mouse model of PTHS exhibits breathing problems similar to PTHS patients. This behavioral deficit is associated with selective loss of putative expiratory parafacial neurons and compromised function of neurons in the retrotrapezoid nucleus that regulate breathing in response to tissue CO<jats:sub>2<\/jats:sub>\/H<jats:sup>+<\/jats:sup>. We also show that central Nav1.8 channels can be targeted pharmacologically to improve respiratory function at the cellular and behavioral levels in <jats:italic>Tcf4<\/jats:italic><jats:sup>tr\/+<\/jats:sup> mice, thus establishing Nav1.8 as a high priority target with therapeutic potential in PTHS.<\/jats:p>","DOI":"10.1038\/s41467-021-26263-2","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T17:43:34Z","timestamp":1634147014000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Disordered breathing in a Pitt-Hopkins syndrome model involves Phox2b-expressing parafacial neurons and aberrant Nav1.8 expression"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0305-1324","authenticated-orcid":false,"given":"C. 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