Project Summary / Abstract Absence seizures occur in pediatric generalized epilepsy and involve excessive synchrony of the thalamocortical neural network. An unexplored possibility is that aberrant activity-dependent myelination contributes to absence seizure progression by promoting network synchrony. A recent discovery is that neuronal activity drives myelin plasticity (changes in myelin structure) in vivo. Myelination, in turn, is a critical determinant of neuronal network synchrony and function. Activity-regulated formation of new myelin requires Brain Derived Neurotrophic Factor (BDNF) signaling through its receptor, TrkB, on oligodendrocyte precursor cells (OPCs). Pathological seizure activity may also induce changes in myelin structure, which in turn could contribute to network dysfunction. This proposal investigates the relationship between absence seizures and activity-dependent myelin plasticity. Preliminary data indicate that absence seizures are associated with abnormally increased myelination in two rodent models with spontaneous absence seizures: Wag/Rij rats (a widely used inbred rat strain) and Scn8a+/mut mice. These mice have a loss of function mutation in SCN8A, similar to children with generalized epilepsy due to loss of function in SCN8A. Both models exhibit increased OPCs and myelin sheath thickness in the anterior corpus callosum. Preventing seizures with ethosuximide prevented the increased callosal myelination, indicating that seizures are required. My hypothesis is that seizure-induced aberrant myelination facilitates excessive synchrony and contributes to seizure burden. In Aim 1, the nature and extent of abnormal myelination in the thalamocortical network will be investigated using magnetization transfer and diffusion-based magnetic resonance imaging of Scn8a+/mut mice. Measurements will be validated by the gold standard method of quantifying myelination, electron microscopy. Aim 2 will determine the role of activity-dependent myelination in thalamocortical hyper-synchrony underlying absence seizures. This will be accomplished by conditionally deleting the TrkB receptor from OPCs in Scn8a+/mut mice specifically during the period of seizure initiation and progression, using a novel mouse line (Scn8a+/mut; trkB fl/fl; PDGFR::Cre). Indices of network synchrony will be measured in acute thalamic slices from Scn8a+/mut mice with or without normal activity-dependent myelination. Aim 3 will determine whether myelin plasticity contributes to seizure burden, by genetically blocking activity-dependent myelination as in Aim 2, and quantifying seizures with EEG. Thus, the proposed studies will use innovative methods to elucidate a novel and potentially paradigm-shifting pathological mechanism in epilepsy, with implications for new therapeutic strategies.