Scn2a deletion improves survival and brain-heart dynamics in the Kcna1-null mouse model of sudden unexpected death in epilepsy (SUDEP)
People with epilepsy have greatly increased probability of premature mortality due to sudden unexpected death in epilepsy (SUDEP). Identifying which patients are most at risk of SUDEP is hindered by a complex genetic etiology, incomplete understanding of the underlying pathophysiology and lack of prognostic biomarkers. Here we evaluated heterozygous Scn2a gene deletion (Scn2a+/-) as a protective genetic modifier in the Kcna1 knockout mouse (Kcna1-/-) model of SUDEP, while searching for biomarkers of SUDEP risk embedded in electroencephalography (EEG) and electrocardiography (ECG) recordings. The human epilepsy gene Kcna1 encodes voltage-gated Kv1.1 potassium channels that act to dampen neuronal excitability whereas Scn2a encodes voltage-gated Nav1.2 sodium channels important for action potential initiation and conduction. SUDEP-prone Kcna1-/- mice with partial genetic ablation of Nav1.2 channels (i.e. Scn2a+/-; Kcna1-/-) exhibited a two-fold increase in survival. Classical analysis of EEG and ECG recordings separately showed significantly decreased seizure durations in Scn2a+/-; Kcna1-/- mice compared with Kcna1-/- mice, without substantial modification of cardiac abnormalities. Novel analysis of the EEG and ECG together revealed a significant reduction in EEG-ECG association in Kcna1-/- mice compared with wild types, which was partially restored in Scn2a+/-; Kcna1-/- mice. The degree of EEG-ECG association was also proportional to the survival rate of mice across genotypes. These results show that Scn2a gene deletion acts as protective genetic modifier of SUDEP and suggest measures of brain-heart association as potential indices of SUDEP susceptibility.
Medical Subject Headings
Animals; Biomarkers; Brain (physiopathology); Death, Sudden; Disease Models, Animal; Electrocardiography; Electroencephalography; Epilepsy (complications, genetics); Genotype; Heart (physiopathology); Heart Rate; Kv1.1 Potassium Channel (genetics, metabolism); Mice; Mice, Knockout; NAV1.2 Voltage-Gated Sodium Channel (genetics, metabolism); Seizures (genetics)
Human molecular genetics
Digital Object Identifier (DOI)
Mishra, Vikas; Karumuri, Bharat K.; Gautier, Nicole M.; Liu, Rui; Hutson, Timothy N.; Vanhoof-Villalba, Stephanie L.; Vlachos, Ioannis; Iasemidis, Leonidas; and Glasscock, Edward, "Scn2a deletion improves survival and brain-heart dynamics in the Kcna1-null mouse model of sudden unexpected death in epilepsy (SUDEP)" (2017). Translational Neuroscience. 1169.