Maladaptive myelination promotes epileptogenesis in absence epilepsy

Summary Neuronal activity can influence the generation of new oligodendrocytes (oligodendrogenesis) and myelination. In health, this is an adaptive process that can increase synchrony within distributed neuronal networks and contribute to cognitive function. We hypothesized that in seizure disorders, aberrant neuronal activity may promote maladaptive myelination that contributes to pathogenesis. Absence epilepsy is a disease defined by increasingly frequent behavioral arrest seizures over time, thought to be due to thalamocortical network hypersynchrony. We tested the hypothesis that activity-dependent myelination resulting from absence seizures promotes epileptogenesis. Using two distinct models of absence epilepsy, Wag/Rij rats and Scn8a +/mut mice, we found increased oligodendrogenesis and myelination specifically within the absence seizure network. These changes are evident only after seizure onset in both models and are prevented with pharmacological inhibition of seizures. Genetic blockade of activity-dependent myelination during epileptogenesis markedly decreased seizure frequency in the Scn8a +/mut mouse model of absence epilepsy. Taken together, these findings indicate that activity-dependent myelination driven by absence seizures contributes to seizure kindling during epileptogenesis.