Abstracts

Rationale:
Activity-dependent myelination supports neurological function in the healthy brain. This process involves Brain Derived Neurotrophic Factor signaling through TrkB receptors on oligodendrocyte precursor cells (OPCs), which prompts their maturation to myelinating oligodendrocytes. We previously discovered that absence seizures induce activity-dependent myelination in the thalamocortical seizure network of a mouse model of generalized epilepsy, Scn8a ^+/-. Myelin plasticity blockade with conditional, inducible deletion of TrkB expression in OPCs in Scn8a ^+/-; TrkB fl/fl; PDGFRα-CreER mice resulted in decreased seizure burden (Knowles et al, Nature Neuroscience 2022). These findings indicate the bidirectional nature of seizure progression and activity-dependent myelination, which prompted us to investigate how increases in myelination alter neuronal network properties to increase seizure susceptibility. We hypothesized that seizure-induced myelination promotes pathological inter and intra hemispheric hypersynchrony, which is characteristic of generalized epilepsy.

Methods:
In Scn8a +/-; TrkB fl/fl; PDGFRα-CreER, we induced a conditional deletion of TrkB expression from OPCs by administering tamoxifen (100 mg/kg) on post-natal day (P)75, thus impairing subsequent myelin plasticity just prior to seizure onset. The mice were implanted with electrodes in the motor and somatosensory cortices (where seizures are maximal) and visual cortices (where seizures are minimal). EEGs were recorded before and after seizures become established on P90 and P180 in Scn8a +/-+/- and Scn8a +/+ mice with normal or impaired myelin plasticity. We then quantified inter- and intrahemispheric EEG coherence for each of the 4 experimental groups.

Results:
At P180, myelin plasticity blockade dramatically reduced spectral power of seizures, inter-hemispheric ictal hypersynchrony in motor and somatosensory cortices, and intra-hemispheric ictal hypersynchrony between somatosensory and visual cortices. Blocking myelin plasticity did not affect interhemispheric visual cortical coherence. There was no significant difference in interictal coherence in any of the experimental groups, and no difference in coherence at P90, prior to seizure progression.

Conclusions:
Our data indicate that activity-dependent myelination is required for ictal hypersynchrony during absence seizures. We hope to build upon this work by developing approaches to restrict aberrant, seizure-induced, activity-dependent myelination without affecting learning-induced myelination.

Funding:
Thank you to the American Epilepsy Society for granting me this amazing opportunity to work in the Knowles lab alongside wonderful mentors. Thank you, also, to the NIH, Cure Epilepsy, Stanford Medicine, Child Neurology Foundation, and the Stanford Maternal and Child Health Research Institute for supporting this work.