Persistent Na current couples spreading depolarization to seizures in gain of function mice.

Spreading depolarization (SD) is a slowly propagating wave of massive cellular depolarization that transiently impairs the function of affected brain regions. While SD typically arises as an isolated hemispheric event, we previously reported that reducing M-type potassium current (I) by ablation of in forebrain excitatory neurons results in tightly coupled spontaneous bilateral seizure-SD complexes in the awake mouse cortex. Here we find that enhanced persistent Na current due to gain-of-function (GOF) mutations in (N1768D/+, hereafter D/+) produces a similar compound cortical excitability phenotype. Chronic DC-band EEG recording detected spontaneous bilateral seizure-SD complexes accompanied by seizures with a profound tonic motor component, which occur predominantly during the light phase and were detected at ages between P33-100. Laser speckle contrast imaging of cerebral blood flow dynamics resolved SD as a bilateral wave of hypoperfusion and subsequent hour-lasting hypoperfusion in cortex in awake head-restrained mice evoked by a PTZ injection. Subcortical recordings in freely moving mice revealed that approximately half of the spontaneous cortical seizure-SD complexes arose with a concurrent SD-like depolarization in the thalamus and delayed depolarization in the striatum. In contrast, SD-like DC potential shifts were rarely detected in the hippocampus or upper pons. Consistent with the high spontaneous incidence , cortical slices from mice showed a raised SD susceptibility, and pharmacological inhibition of persistent Na current (I), which is enhanced in neurons, inhibited SD generation in cortical slices as well as in head-fixed mice , indicating that I contributes to SD susceptibility. Ca imaging studies using acute brain slices expressing genetic Ca sensor (Thy1-GCAMP6s) demonstrated that pharmacological activation of I suppressed Ca spikes and SD, whereas an I inhibitor strongly increased the frequency of hippocampal Ca spikes in , but not WT slices, suggesting that I restrains the GOF hyperexcitability. Together, our study identifies a cortical SD phenotype in GOF mice shared with the -cKO model of developmental epileptic encephalopathy, and reveals that an imbalance of non-inactivating inward and outward tonic membrane currents bidirectionally modulates spatiotemporal SD susceptibility.