Scn2a-Null Heterozygosity Improves Survival and Modifies Neurocardiac Interaction in the Kcna1-Null Mouse Model of SUDEP

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality, but its genetic etiology is largely unknown and likely complex involving multiple genes. The Kcna1 gene encodes Kv1.1 potassium channels that act to dampen neuronal excitability whereas the Scn2a gene encodes Nav1.2 sodium channels important for action potential conduction. We tested the hypothesis that subclinical Scn2a heterozygosity reduces SUDEP incidence in Kcna1-null mice of SUDEP, by suppressing neurocardiac dysfunction associated with the absence of Kv1.1 channels. SUDEP-prone Kcna1-null mice exhibited about a 50% increase in lifespan when heterozygous for the Scn2a-null allele, that is Scn2a
^+/-
, Kcna1
^-/-
. In simultaneous video electroencephalography (EEG)- electrocardiography (ECG) recordings, Scn2a heterozygosity did not eliminate seizures in Kcna1
^-/-
mice, but seizure burden was partially reduced due to a significant reduction in seizure durations. Analysis of beat-to-beat heart rate variability (HRV) revealed that Kcna1
^-/-
and Scn2a
^+/-
, Kcna1
^-/-
mice exhibit similarly high RMSSD (Root Mean Square of the Successive Differences), suggesting the functional interactions between the two mutations do not involve significant alteration of parasympathetic tone. Moreover, analysis of EEG-ECG interaction dynamics revealed a significantly higher degree of association between brain and cardiac activity in double mutant mice compared to Kcna1
^-/-
animals for several different measures, suggesting that Scn2a-null heterozygosity reduces SUDEP risk by altering neural control of the heart. These findings expand our understanding of the complex genetic interactions underlying SUDEP and identify EEG-ECG association as a potential new biomarker of SUDEP susceptibility.