Abstracts

Rationale: Spreading depolarization (SD) is a slowly moving massive cellular depolarization of neurons and glia. SD contributes to migraine with aura and is also associated with deterioration neurological deterioration following head injuries. We have recently shown that SD is spontaneously generated in the epileptic mouse cortex in an underlying molecular deficit-dependent manner. Scn1a/Nav1.1 encodes a pore-forming subunit of voltage-gated Na⁺ channels expressed in both excitatory and inhibitory neurons in the cerebral cortex. Mutations in Scn1a mutations result in deleterious infant onset epilepsy with various comorbidities (Dravet syndrome) and hemiplegic migraine type-3 depending on the mutation types. Currently, cortical SD susceptibility and its potential role in the epilepsy phenotype in Scn1a deficiency are not well understood.

Methods: We analyzed spontaneous SD susceptibility by monitoring awake young adult heterozygous mutant mice (Scn1a^R1407X/+, hereafter Scn1a-MT) and their wild-type littermates (Scn1a-WT) using chronic DC recordings. We also analyzed whether the induction of a febrile seizure can modulate the frequency of occurrence of spontaneous seizures and SD. SD thresholds were determined using in vitro cortical slices prepared from Scn1a-MT and WT littermates.

Results: Chronic DC recording detected spontaneous seizures, SDs, and seizure/SD clusters in Scn1a MT in mice with large variability between animals. In some Scn1a MT mice, spontaneous cortical SD was the sole pathological manifestation. Most febrile seizures were associated with short latency postictal SD events in Scn1a MT, but not in WT control animals. The presence of postictal SD was associated with increases in both seizure and SD frequencies. On the other hand, mutant without SD following an induced febrile seizure showed less pronounced effects. In vitro SD threshold tests revealed no overt difference between Scn1aWT and MT cortical slices, suggesting that the appearance of spontaneous SD is not due to the lowered intrinsic SD thresholds.

Conclusions: These results indicate that SD is a significant epileptic phenotype of the Scn1a deficiency mouse model. SD has a context-dependent modulatory effect on epilepsy; spontaneous SDs are relatively benign while the appearance of SD following a febrile seizure is associated with exacerbation of cortical hyperexcitation.

Funding: Please list any funding that was received in support of this abstract.: American Heart Association career development grant 19CDA34660056 (I.A.), Curtis Hankamer Basic Research Fund at Baylor College of Medicine (IA), NIH Center for SUDEP Research (NS090340 and NS29709, J.L.N), and Blue Bird Circle Foundation (J.L.N.).