Characterization of a Novel Knock-in Mouse Model of KCNT1 Epileptic Encephalopathy (P2.273)

Objective: To characterize a knock-in mouse model of KCNT1 epileptic encephalopathy. Background: Epilepsy of infancy with migrating focal seizures (EIMFS) is a severe form of childhood epilepsy characterized by an early onset, refractory seizures, global developmental delay and cognitive disability. De novo mutations of the sodium activated potassium channel gene KCTN1 have been found in up to 50% of the patients. The p.Pro924Leu mutation has been found in 2 patients with EIMFS, in vitro studies in heterologous expression systems have shown a significant gain of function effect of the mutation, resulting in large potassium currents compared to the wild type (WT) channel. Design/Methods C57BL/6 mice transgenic for the p.P924L mutation were generated using the CRISPR/Cas system. Video electrocorticogram(video/ECoG) analysis, thermal and chemoconvulsant (Pentylenetetrazole and Loxapine) tests were performed to assess seizure susceptibility. Locomotor activity and nest building behavior were evaluated to screen for motor dysfunction and cognitive impairment. Results: Heterozygous Kcnt1(L/+) mice display no increased susceptibility to thermal or chemically induced seizures compared to Kcnt1 WT(+/+) mice. No differences were found on the video/ECoG, nesting and locomotor activity for Kcnt1(L/+) and Kcnt1 WT(+/+) mice. In contrast, homozygous Kcnt1(L/L) mice are smaller in size, exhibit spontaneous tonic clonic seizures, impaired nesting behavior and a shortened lifespan. ECoG analysis revealed ictal discharges that coincide with convulsive seizures as well as interictal spikes in these mice. Conclusions: Kcnt1(L/L) mice provide a model of epileptic encephalopathy that will be valuable for studying the in vivo effects of gain of function KCNT1 mutations and the response to targeted therapeutic interventions. Disclosure: Dr. Burbano has nothing to disclose. Dr. Lin has nothing to disclose. Dr. Jancovsky has nothing to disclose. Dr. Richards has nothing to disclose. Dr. Gazina has nothing to disclose. Dr. Maljevic has nothing to disclose. Dr. Reid has nothing to disclose. Dr. Petrou has received compensation for serving on the Board of Directors of Pairnomix, Praxis Precision Medicine, RogCon. Dr. Petrou holds stock and/or stock options in Pairnomix, Praxis Precision Medicine, RogCon, which sponsored research in which Dr. Petrou was involved as an investigator. Dr. Petrou has received research support from Praxis Precision Medicine, RogCon.