Progressive central cardiorespiratory rate downregulation and intensifying epilepsy lead to sudden unexpected death in epilepsy in mouse model of the most common human ATP1A3 mutation.

Abstract

Objective: This study was undertaken to test the following hypotheses in the Atp1a3^Mashl/+ mouse (which carries the most common human ATP1A3 (the major subunit of the neuronal Na⁺/K⁺-adenosine triphosphatase [ATPase]) mutation, D801N): sudden unexpected death in epilepsy (SUDEP) occurs during seizures and is due to terminal apneas in some and due to lethal cardiac arrhythmias in others; and Atp1a3^Mashl/+ mice have central cardiorespiratory dysregulation and abnormal respiratory drive.

Methods: Comparison was made of littermate wild-type and Atp1a3^Mashl/+ groups using (1) simultaneous in vivo video-telemetry recordings of electroencephalogram, electrocardiogram, and breathing; (2) whole-body plethysmography; and (3) hypoglossal nerve recordings.

Results: In Atp1a3^Mashl/+ mice, (1) SUDEP consistently occurred during seizures that were more severe than preterminal seizures; (2) seizure clustering occurred in periods preceding SUDEP; (3) slowing of breathing rate (BR) and heart rate was observed preictally before preterminal and terminal seizures; and (4) the sequence during terminal seizures was as follows: bradypnea with bradycardia/cardiac arrhythmias, then terminal apnea, followed by terminal cardiac arrhythmias. Compared to wild-type, mutants showed (1) abnormal resting BR variability but no difference in cardiac PR, QRS, QTc, or RR intervals; (2) abnormal hypoglossal nerve firing in response to hypoxia; and (3) abnormal whole-body plethysmography, consisting of baseline predisposition to apnea and abnormal responses to respiratory challenge.

Significance: Atp1a3^Mashl/+, an alternating hemiplegia of childhood (AHC) model, is also a revealing SUDEP model of Na⁺/K⁺-ATPase mutation resulting in abnormal central respiratory drive and in progressive cardiorespiratory dysregulation concurrent with worsening epilepsy. SUDEP results from seizure-triggered bradypnea/bradycardia followed by terminal apnea, then terminal cardiac arrhythmias. Because many epilepsy/SUDEP models of other etiologies manifest secondary ATPase deficiency, future studies in those models may benefit from considering possible contributions of ATPase dysfunction to SUDEP in those models too.