Abstracts

This abstract has been invited to present during the Basic Mechanisms platform session

Rationale: In the healthy brain, neuronal activity-regulated myelination is adaptive, increasing network synchrony to support neurological function. We demonstrated (Knowles et al, Nature Neuroscience 2022) that myelin plasticity can also become dysregulated by absence seizures and promote epilepsy progression. We hypothesized that aberrant myelination occurs in large territories of white matter overlapping absence seizure activity, and promotes pathological hypersynchrony of cortical regions.

Methods: Studies were performed in a mouse model of generalized epilepsy, Scn8a^+/mut, which exhibits spontaneous onset and progression of bilateral, frontoparietal 4-8 Hz absence seizures. In Scn8a^+/mut mice and WT littermates, we mapped g-ratios (myelin sheath thickness per axon diameter) with qMTI (quantitative magnetization transfer in conjunction with diffusion MRI) in major white matter tracts. We measured coherence of interhemispheric somatosensory and visual cortical EEG. Given that Brain Derived Neurotrophic Factor (BDNF) signaling through oligodendrocyte precursor cell (OPC) TrkB receptors is required for activity-dependent myelination, we induced OPC-specific deletion of TrkB receptors during seizure progression in Scn8a^+/mut mice (OPC cKO) to determine the contribution of myelin plasticity to EEG coherence.

Results: With qMTI, we found decreased g-ratios (indicating increased myelin sheath thickness) across the longitudinal extent of the anterior corpus callosum, connecting frontal and parietal regions of the bilateral hemispheres. By contrast, g-ratios in the posterior corpus callosum and hippocampal commissures, connecting regions where absence seizures are not prominent, were unchanged. qMTI estimates of g-ratio were validated with the gold standard, electron microscopy. qMTI-based g-ratio measurements from internal capsules and anterior commissure are in process. Genetic blockade of activity-dependent myelination in Scn8a^+/mut mice markedly decreased seizure progression and decreased ictal somatosensory EEG coherence. Conversely, blocking myelin plasticity had no effect on ictal EEG coherence between visual cortices, connected by the posterior corpus callosum. 

Conclusions: Aberrant myelination in Scn8a^+/mut mice mirrors the anatomical distribution of absence seizures, and promotes interhemispheric hypersynchrony and seizure progression. Maladaptive myelination is a newly recognized pathogenic mechanism which predisposes brain networks to hypersynchronous patterns of activity such as seizures.

Funding: The authors gratefully acknowledge support from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (R01NS092597 to M.M, K12NS098482 and NIH/NINDS K08NS119800 to J.K.K., R01NS034774 and R01NS117150 to J.H.), NIH Director’s Pioneer Award (DP1NS111132 to M.M.), Robert J. and Helen C. Kleberg Foundation (to M.M.), Stanford Maternal and Child Health Research Institute (to M.M. and J.K.K.), Bio-X Institute (to M.M. and J.K.K.), Cancer Research UK (to M.M.), American Epilepsy Society, CURE Epilepsy Foundation and Child Neurology Foundation (to J.K.K.), Stanford BioX (to T.S. and G.C.).