Rationale:
Spreading depolarization (SD) is a massive self-regenerative wave of near complete cellular depolarization associated with regional neurological deficits. We have previously reported a unique seizure-SD phenotype detected in Kcnq2 conditional knock-out (cKO) mice that appeared as a tightly coupled, bilaterally simultaneous seizure-SD complex (Aiba 2021). However, that model is based on conditional deletion of both Kcnq2 alleles exclusively from excitatory neurons using an Emx1-Cre driver, and it is not known whether this atypical pattern is an artificial result of the conditional KO model. In the present study, we characterized the SD phenotype of heterozygous Scn8a gain-of-function (GoF) mutant mice which carry a patient-derived missense mutation (N1768D/+). We anticipated that increasing the persistent Na
+ current in these channels could mirror the loss of non-inactivating potassium M-current mediated by Kcnq-channels.
Methods:
The spontaneous seizure and SD phenotype was characterized with chronic EEG monitoring in awake mice. The cortical SD threshold was also measured
in vitro using a KCl thresholding test.
Results:
Chronic cortical EEG recordings in the Scn8a GoF mice detected significant numbers of spontaneous seizure-SD complexes during the P30-55 age period and more isolated seizures at later stage. The seizure-SD complex detected in this model had the same electrophysiological features as those detected in Kcnq2-cKO mice in our previous study, such as close temporal coupling of seizure and SD and bilateral simultaneous appearance in all four EEG channels. Similar to the Kcnq2-cKO mouse cortex, cortical tissue isolated from the Scn8a GoF mouse showed a higher SD susceptibility to increased bath KCl.
Conclusions:
Our preliminary characterization of GoF Scn8a mice identified a distinctive cortical SD phenotype similar to that of the Kcnq2-cKO mice, and confirmed that this seizure-SD complex is shared in a genomic, human disease relevant, Scn8a mutant model. The results also suggest that loss of Kcnq mediated M-current and gain of sodium current may share part of their electro-cortical pathology.
Funding: NIH, American Epilepsy Society, The Blue Bird Circle.