Abstracts

Rationale: Epileptic encephalopathy type 26 (EIEE26) is caused by mutations in KNCB1. One of the original mutations identified, G379R, is located within the pore selectivity domain. The patient initially had infantile spasms with later progression to Lennox-Gastaut syndrome. At onset of infantile spasms, the patient had hypsarrhythmia on EEG which evolved into mixed multifocal and diffuse spikes and polyspikes and slow wave. Here we investigate interictal epileptiform discharges in a novel Kcnb1 G379R mouse model. Methods: Mice were generated using CRISPR/Cas9 genome engineering and maintained on the C57BL/6J background.  Kcnb1^R/+, Kcnb1^R/R, and wild-type (WT) littermate controls of both sexes were evaluated (n= WT: 2 males, 3 females; Kcnb1^R/+: 3 males, 1 female; Kcnb1^R/R: 2 males, 1 female).  At postnatal day 21-23 (P21-23) three channel prefabricated EEG head mounts were implanted.  After 4-5 days of recovery from surgery, continuous video-EEG was collected for at least two weeks for each subject.  Epileptiform activity was scored manually by an observer blinded to genotype from 6-hour recordings on 4 different days of recording.  Epileptiform activity was subcategorized as interictal epileptiform discharges, spike and slow-wave complexes, polyspikes, and repetitive interictal epileptiform discharges. Results: Continuous video-EEG recordings from Kcnb1^R/+ and Kcnb1^R/R mice revealed abnormal interictal epileptiform discharges. There was a significant increase in the frequency of epileptiform discharges including spikes, sharp waves, and polyspikes per hour in the heterozygous (Kcnb1^R/+) or homozygous (Kcnb1^R/R) mice compared to WT (p<0.05, ANOVA). Finally repetitive interictal epileptiform discharges in slow spike wave (0.5-2 Hz) runs occurred lasting up to 3 minutes in duration in Kcnb1^R/+ and Kcnb1^R/R mice but were not observed in wild-type littermates. Conclusions: The video-EEG from Kcnb1^R/+ and Kcnb1^R/R mice display several interictal epileptiform abnormalities.  This mouse model recapitulates many of the EEG features observed on EEGs from the patient during childhood and may be useful for evaluating potential treatments. Funding: Funding Support: R01 NS053792