{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T11:17:11Z","timestamp":1782386231264,"version":"3.54.5"},"reference-count":40,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2018,1,12]],"date-time":"2018-01-12T00:00:00Z","timestamp":1515715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS072179"],"award-info":[{"award-number":["NS072179"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS085389"],"award-info":[{"award-number":["NS085389"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002736","name":"Citizens United for Research in Epilepsy","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002736","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000097","name":"National Center for Research Resources","doi-asserted-by":"publisher","award":["G20RR024001"],"award-info":[{"award-number":["G20RR024001"]}],"id":[{"id":"10.13039\/100000097","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2018,2]]},"abstract":"Summary<\/jats:title>Objective<\/jats:title>Increased breathing rate, apnea, and respiratory failure are associated with sudden unexpected death in epilepsy (SUDEP<\/jats:styled-content>). We recently demonstrated the progressive nature of epilepsy and mortality in Kcna1<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice, a model of temporal lobe epilepsy and SUDEP<\/jats:styled-content>. Here we tested the hypothesis that respiratory dysfunction progresses with age in Kcna1<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice, thereby increasing risk of respiratory failure and sudden death (SD<\/jats:styled-content>).<\/jats:p><\/jats:sec>Methods<\/jats:title>Respiratory parameters were determined in conscious mice at baseline and following increasing doses of methacholine (MC<\/jats:styled-content>h) using noninvasive airway mechanics (NAM<\/jats:styled-content>) systems. Kcna1<\/jats:italic>+\/+<\/jats:italic><\/jats:sup>, Kcna1<\/jats:italic>+\/\u2212<\/jats:sup>, and Kcna1<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> littermates were assessed during 3 age ranges when up to ~30%, ~55%, and ~90% of Kcna1<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice have succumbed to SUDEP<\/jats:styled-content>: postnatal day (P) 32\u201036, P40\u201046, and P48\u201056, respectively. Saturated arterial O2<\/jats:sub> (SaO2<\/jats:sub>) was determined with pulse oximetry. Lung and brain tissues were isolated and Kcna1<\/jats:italic> gene and protein expression were evaluated by reverse transcriptase quantitative polymerase chain reaction (RT<\/jats:styled-content>\u2010qPCR)<\/jats:styled-content> and Western blot techniques. Airway smooth muscle responsiveness was assessed in isolated trachea exposed to MC<\/jats:styled-content>h.<\/jats:p><\/jats:sec>Results<\/jats:title>Kcna1<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice experienced an increase in basal respiratory drive, chronic oxygen desaturation, frequent apnea\u2010hypopnea (A\u2010H), an atypical breathing sequence of A\u2010H\u2010tachypnea\u2010A\u2010H, increased tidal volume, and hyperventilation induced by MC<\/jats:styled-content>h. The MC<\/jats:styled-content>h\u2010provoked hyperventilation was dramatically attenuated with age. Of interest, only Kcna1<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice developed seizures following exposure to MC<\/jats:styled-content>h. Seizures were provoked by lower concentrations of MC<\/jats:styled-content>h as Kcna1<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice approached SD<\/jats:styled-content>. MC<\/jats:styled-content>h\u2010induced seizures experienced by a subset of younger Kcna1<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice triggered death. Respiratory parameters of these younger Kcna1<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice<\/jats:italic> resembled older near\u2010SD <\/jats:styled-content>Kcna1<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. Kcna1<\/jats:italic> gene and protein were not expressed in Kcna1<\/jats:italic>+\/+<\/jats:italic><\/jats:sup> and Kcna1<\/jats:italic>+\/\u2212<\/jats:sup> lungs, and MC<\/jats:styled-content>h\u2010mediated airway smooth muscle contractions exhibited similar half\u2010maximal effective concentration( EC<\/jats:styled-content>50<\/jats:sub>) in isolated Kcna1<\/jats:italic>+\/+<\/jats:italic><\/jats:sup> and Kcna1<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> trachea.<\/jats:p><\/jats:sec>Significance<\/jats:title>The Kcna1<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> model of SUDEP<\/jats:styled-content> exhibits progressive respiratory dysfunction, which suggests a potential increased susceptibility for respiratory failure during severe seizures that may result in sudden death.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.13971","type":"journal-article","created":{"date-parts":[[2018,1,12]],"date-time":"2018-01-12T05:47:18Z","timestamp":1515736038000},"page":"345-357","source":"Crossref","is-referenced-by-count":57,"title":["Respiratory dysfunction progresses with age in Kcna1<\/i>\u2010null mice, a model of sudden unexpected death in epilepsy"],"prefix":"10.1111","volume":"59","author":[{"given":"Kristina A.","family":"Simeone","sequence":"first","affiliation":[{"name":"Department of Pharmacology Creighton University School of Medicine Omaha NE USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jodi","family":"Hallgren","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Creighton University School of Medicine Omaha NE USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles S.","family":"Bockman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Creighton University 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