| First Author | Simeone KA | Year | 2018 |
| Journal | Epilepsia | Volume | 59 |
| Issue | 2 | Pages | 345-357 |
| PubMed ID | 29327348 | Mgi Jnum | J:272147 |
| Mgi Id | MGI:6282662 | Doi | 10.1111/epi.13971 |
| Citation | Simeone KA, et al. (2018) Respiratory dysfunction progresses with age in Kcna1-null mice, a model of sudden unexpected death in epilepsy. Epilepsia 59(2):345-357 |
| abstractText | OBJECTIVE: Increased breathing rate, apnea, and respiratory failure are associated with sudden unexpected death in epilepsy (SUDEP). We recently demonstrated the progressive nature of epilepsy and mortality in Kcna1(-/-) mice, a model of temporal lobe epilepsy and SUDEP. Here we tested the hypothesis that respiratory dysfunction progresses with age in Kcna1(-/-) mice, thereby increasing risk of respiratory failure and sudden death (SD). METHODS: Respiratory parameters were determined in conscious mice at baseline and following increasing doses of methacholine (MCh) using noninvasive airway mechanics (NAM) systems. Kcna1(+/+) , Kcna1(+/-) , and Kcna1(-/-) littermates were assessed during 3 age ranges when up to ~30%, ~55%, and ~90% of Kcna1(-/-) mice have succumbed to SUDEP: postnatal day (P) 32-36, P40-46, and P48-56, respectively. Saturated arterial O2 (SaO2 ) was determined with pulse oximetry. Lung and brain tissues were isolated and Kcna1 gene and protein expression were evaluated by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Western blot techniques. Airway smooth muscle responsiveness was assessed in isolated trachea exposed to MCh. RESULTS: Kcna1(-/-) mice experienced an increase in basal respiratory drive, chronic oxygen desaturation, frequent apnea-hypopnea (A-H), an atypical breathing sequence of A-H-tachypnea-A-H, increased tidal volume, and hyperventilation induced by MCh. The MCh-provoked hyperventilation was dramatically attenuated with age. Of interest, only Kcna1(-/-) mice developed seizures following exposure to MCh. Seizures were provoked by lower concentrations of MCh as Kcna1(-/-) mice approached SD. MCh-induced seizures experienced by a subset of younger Kcna1(-/-) mice triggered death. Respiratory parameters of these younger Kcna1(-/-) mice resembled older near-SD Kcna1(-/-) mice. Kcna1 gene and protein were not expressed in Kcna1(+/+) and Kcna1(+/-) lungs, and MCh-mediated airway smooth muscle contractions exhibited similar half-maximal effective concentration( EC50 ) in isolated Kcna1(+/+) and Kcna1(-/-) trachea. SIGNIFICANCE: The Kcna1(-/-) model of SUDEP exhibits progressive respiratory dysfunction, which suggests a potential increased susceptibility for respiratory failure during severe seizures that may result in sudden death. |
