Kcna2 Gain-of-Function Mutation Leads To Sudden Unexpected Death In Epilepsy

Objective: One of the frequently mutated genes in epileptic encephalopathy is KCNA2, which encodes the Kv1.2 subunit of voltage-gated Kv1 potassium channels. The pathogenic mechanisms underlie epileptic seizures remains unknown. Methods: We investigated spontaneous epileptiform events using electroencephalography-electrocardiography and video monitoring from a heterozygous knock-in mouse model carrying the Kv1.2 p.R297Q pathogenic variant. To gain a better understanding of the cellular mechanisms underlying network dysfunction, we performed single-nucleus RNA sequencing from mouse cortex samples (ages 5 weeks). Results: EEG recordings in mice (ages 5 weeks) confirmed sudden unexpected death in epilepsy (SUDEP) as severe tonic seizures immediately preceding loss of brain activity and death. Within 60 seconds after lethal seizure onset, heart rate abruptly declined. The standard deviation of the beat–to–beat intervals and the root mean square of successive beat-to-beat differences were elevated in R297Q mice compared with controls, providing evidence of abnormally high parasympathetic tone in mice lacking Kv1.2 channels. Furthermore, we found that intratelencephalic projection neurons exhibited the strongest upregulations in cell–cell interaction, including but not limited to VIP and CCK pathway. Significance: The Kcna2 gain-of-function mutation p.R297Q induces SUDEP in mic, and sudden death is due in part to aberrant parasympathetic neurotransmission.