Sudden unexpected death in a mouse model of Dravet syndrome
Franck Kalume, Ruth E. Westenbroek, Christine S. Cheah, Frank H. Yu, John C. Oakley, Todd Scheuer, William A. Catterall
Franck Kalume, Ruth E. Westenbroek, Christine S. Cheah, Frank H. Yu, John C. Oakley, Todd Scheuer, William A. Catterall
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Research Article

Sudden unexpected death in a mouse model of Dravet syndrome

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in intractable epilepsies, but physiological mechanisms that lead to SUDEP are unknown. Dravet syndrome (DS) is an infantile-onset intractable epilepsy caused by heterozygous loss-of-function mutations in the SCN1A gene, which encodes brain type-I voltage-gated sodium channel NaV1.1. We studied the mechanism of premature death in Scn1a heterozygous KO mice and conditional brain- and cardiac-specific KOs. Video monitoring demonstrated that SUDEP occurred immediately following generalized tonic-clonic seizures. A history of multiple seizures was a strong risk factor for SUDEP. Combined video-electroencephalography-electrocardiography revealed suppressed interictal resting heart-rate variability and episodes of ictal bradycardia associated with the tonic phases of generalized tonic-clonic seizures. Prolonged atropine-sensitive ictal bradycardia preceded SUDEP. Similar studies in conditional KO mice demonstrated that brain, but not cardiac, KO of Scn1a produced cardiac and SUDEP phenotypes similar to those found in DS mice. Atropine or N-methyl scopolamine treatment reduced the incidence of ictal bradycardia and SUDEP in DS mice. These findings suggest that SUDEP is caused by apparent parasympathetic hyperactivity immediately following tonic-clonic seizures in DS mice, which leads to lethal bradycardia and electrical dysfunction of the ventricle. These results have important implications for prevention of SUDEP in DS patients.

Authors

Franck Kalume, Ruth E. Westenbroek, Christine S. Cheah, Frank H. Yu, John C. Oakley, Todd Scheuer, William A. Catterall

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Figure 3

Frequency of AV block.

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Frequency of AV block. Increased interictal frequency of AV blocks in DS...
Increased interictal frequency of AV blocks in DS mice and forebrain interneuron-specific Scn1a-KO (F/+:Dlx-Cre+) mice, but not in cardiac-specific Scn1a-KO (F/+:MCre+) mice. The 8 hours of continuous video-EEG-ECG recordings were considered for assessments of AV blocks. ECG traces were visually inspected to identify these arrhythmias. (A) Representative simultaneous resting EEG-ECG records from a DS mouse showing regular ECG rhythm and a type-2, second-degree AV block, characterized by skipped QRS complexes without prolongation of preceding PR intervals. All preceding PR intervals in this figure had identical duration, 30.9 ms. (B) Magnified segments of the traces in A. Arrowhead indicates an example of a P wave. (C) Bar graph of interictal AV block frequencies in Scn1a mutant mice and respective control mice illustrating higher frequency of AV blocks in DS (2.24 ± 1.2 vs. 0.6 ± 0.4 AV blocks/h in controls) and F/+:Dlx-Cre+ mice (1.5 ± 0.2 AV blocks/h vs. 0.7 ± 0.5 AV blocks/h in controls), not in F/+:MCre+ mice (0.8 ± 0.5 AV blocks/h vs. 0.7 ± 0.6 AV blocks/h in controls). *P < 0.05.