Abstracts

In the healthy brain, activity-regulated myelin plasticity is adaptive and supports optimal neurological function and learning. By contrast, we previously showed that absence seizures also induce myelin plasticity, which maladaptively promotes epilepsy progression (Knowles et al., Nature Neuroscience, 2022). The anatomical extent and neurophysiological mechanisms underlying maladaptive myelination that promotes generalized epilepsy remain to be established.

Scn8a+/- mice, which exhibit spontaneous, progressive absence seizures, were used. Structural changes were assessed using brain wide quantitative magnetization transfer in conjunction with diffusion MRI (MRI myelin mapping) to map g-ratio (myelin sheath thickness per axon diameter; Chau*, Knowles* et al, 2023) in the corpus callosum and internal capsules of Scn8a^+/- mice and wild-type littermates; findings were confirmed with electron microscopy (EM). Neurophysiological mechanisms were evaluated by compound action potential recordings in acute brain slices, and by EEG coherence and power spectral analysis in mice. We used Scn8a+/- mice with and without OPC-specific deletion of the TrkB receptor for BDNF (Scn8a+/+;TrkB^fl/fl;PDGFRa::Cre mice, Scn8a+/- OPC TrkB cKO), as OPC TrkB cKO was previously shown to prevent activity-regulated myelination.

In Scn8a+/- mice with established seizures (P45–51), quantitative MRI revealed decreased g-ratios (reflecting increased myelin thickness per axon diameter) along the anterior and middle corpus callosum (CC), confirmed with EM. By contrast, no changes were observed in the posterior corpus callosum, where absence seizures are minimal, or in the internal capsules (Fig. 1a). No g-ratio differences were detected prior to seizure onset (P21). Consistent with these structural findings, increased conduction velocity was observed in the body of corpus callosum (but not in splenium or internal capsule) post-seizure (P45, Fig 1b,c,d), whereas pre-seizure (P21) mice showed no differences. Myelin plasticity blockade in Scn8a+/- OPC TrkB cKO mice prevented seizure-induced increase of callosal conduction in body of CC, and markedly reduced interhemispheric ictal hypersynchrony in somatosensory corticies (Fig 1g). Scn8a+/- mice with intact myelin plasticity exhibited spontaneous ~8 Hz absence seizures, while OPC cKO mice showed a dramatic reduction in seizure burden, ictal spectral power (Fig 1 i-l) and ictal coherence by 6 months.

Our findings establish seizure-induced myelination of the anterior corpus callosum as a novel disease mechanism in generalized epilepsy and moreover point to a previously unappreciated role for maladaptive, anterior callosal structural and functional plasticity in epilepsy progression.