Abstracts

Rationale: Central nervous system myelination is a dynamic process occurring throughout the mammalian lifespan, requiring proliferation of oligodendrocyte precursor cells (OPCs) and their differentiation into mature oligodendrocytes, which ensheath neuronal axons to form mature myelin. Recent evidence indicates that physiological neuronal activity promotes adaptive myelination in vivo, a process required for some forms of learning. It is likely that seizure activity also alters myelin, with possible implications for cognitive function and epileptogenesis, but this has not been thoroughly investigated. The presence of diffusion tensor imaging (DTI) abnormalities in the brains of patients with various forms of epilepsy, including absence epilepsy, further indicates that seizures may alter myelin. Wag/Rij rats, a genetic model of childhood absence epilepsy, were previously shown to have DTI abnormalities in the anterior corpus callosum. Our hypothesis is that recurrent seizures alter OPC proliferation and myelin formation.  Methods: We quantified OPC number using unbiased stereology in the anterior corpus callosum of Wag/Rij and Wistar (control) rats at 1.5 months (prior to seizure onset) and 6 months of age (age at which maximal daily seizure frequency is reached). Myelin sheath thickness was quantified in the same callosal region using electron microscopy. In ongoing/preliminary studies, similar methods are being used to assess myelin structure in the corpus callosum of a second model of absence epilepsy: mice heterozygous for the med (Scn8a loss of function) mutation and wildtype littermates. Results: OPC number was significantly increased in the anterior corpus callosum of 6 month old Wag/Rij relative to Wistar (p=0.016), whereas OPC number was identical in 1.5 month old Wag/Rij and Wistar (n=3-4 rats per group). In the same anatomical area, myelin sheath thickness was increased (p=0.005) as demonstrated by decreased g-ratios in 6 month old Wag/Rij rats relative to Wistar controls (n= 3 rats per group). In preliminary ongoing studies, similar trends are seen in OPC number in mice heterozygous for the med mutation and wildtype littermates (n=4-6 mice per group). Conclusions: Increased callosal myelination is present in at least two rodent models of absence epilepsy and may alter circuit function, contibuting to cognitive impairment and/or increase seizure frequency. Ongoing and future studies will assess the degree to which seizures are necessary for myelin microstructural abnormalities, and the impact of myelin abnormalities upon callosal conduction velocity.  Funding: American Epilepsy Society Clinical Translational Research Fellowship, 2016-2017