A hyperthermic seizure unleashes a surge of spreading depolarizations inScn1adeficient mice

Abstract

Objective: Spreading depolarization (SD) is a massive wave of cellular depolarization that slowly migrates across brain gray matter. SD is frequently generated following brain injury and is associated with various acute and chronic neurological deficits. Here we report that spontaneous cortical SD waves are a common EEG abnormality in the Scn1a deficient mouse model (Scn1a+/R1407X). Method: Chronic DC-band EEG recording detected SDs, seizures, and seizure-SD complexes during prolonged monitoring in awake adult Scn1a+/R1407X mice. The effect of hyperthermic seizure and memantine was tested. Results: The spontaneous incidence of events is low and varied among animals, but SDs outnumber seizures. SD waves almost always spread unilaterally from parietal to frontal cortex. On average, spontaneous SD frequency robustly increased by 4.2-fold following a single hyperthermia-evoked seizure, persisting for days to a week without altering the kinetics of individual events. Combined video image and electromyogram analyses revealed that a single interictal SD is associated with prodromal motor activation followed by minutes-lasting immobility upon invasion of frontal cortex. Similar behavioral sequelae also appeared during postictal SD. Memantine treatment was effective in preventing SD exacerbation when given before and after the hyperthermic seizure, suggesting chronic activation of NMDA-receptor contributed to the prolonged SD aftermath. Interpretation: Our results reveal that cortical SD is a prominent electro-behavioral phenotype in this Scn1a deficient mouse model, and SD frequency is robustly sensitive to hyperthermic seizure induced mechanisms likely involving excess NMDAR signaling. The high susceptibility to SD may contribute to co-morbid pathophysiology in developmental epileptic encephalopathy.

Determining the Spread: Potential Biomarkers and Treatment for Seizure-Induced-Spreading Depolarization in a Mouse Model of Genetic Epilepsy

“…Aiba and colleagues 7 examined the spontaneous incidence and related semiology of SD in adult Scn1a +/RX mice. Scn1a +/RX and WT littermates were monitored using DC-band chronic EEG and infrared video.…”