Respiratory dysfunction progresses with age in Kcna1-null mice, a model of sudden unexpected death in epilepsy

Summary

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.

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