Abstracts

Rationale: Activity-dependent myelination modulates neural network function, enabling adaptation. This process involves oligodendrogenesis (proliferation and maturation of oligodendrocyte precursor cells, OPCs), requiring brain-derived neurotrophic factor (BDNF) signaling through its receptor, TrkB, on OPCs as well as epigenetic changes that can be blocked with histone deacetylase inhibitors such as trichostatin A (TSA). The impact of pathological neuronal activity in the form of seizures upon myelination, and the potential role of myelin plasticity in seizure pathogenesis, are poorly understood. We hypothesized that absence seizures might induce aberrant activity-dependent myelination that contributes to pathological network change and seizure progression.

Methods: We used Wag/Rij rats and Scn8a+/mut mice (bearing a loss of function mutation in Nav1.6), which develop spontaneous absence seizures during well-defined periods of seizure progression (increasing seizure frequency). We used unbiased stereology and electron microscopy to assess oligodendrogenesis and myelin structure in the body of the corpus callosum (within the seizure network). Vehicle (VEH) or ethosuximide (ETX, 300 mg/kg/day) was administered to determine impact of seizures upon myelin structure. We generated Scn8a+/mut mice with deletion of TrkB specifically from OPCs (Scn8a+/mut; TrkBfl/fl; PDGFRA::Cre-ER mice, designated as Scn8a+/mut OPC cKO), induced with tamoxifen given post-natal day (P)21-23. In separate studies, Scn8a+/mut mice were treated with TSA, 10mg/kg daily. Seizures were quantified with EEG. In all graphs, each dot represents measurements from 1 animal. Data were analyzed with ANOVA and post-hoc Sidak’s or Tukey’s test, correcting for multiple comparisons. *p< 0.05, **p< 0.01, ***p< 0.001, n.s. non-significant.