Myelin plasticity: a novel mechanism of generalized epilepsy

The National Institute of Neurological Disorders and Stroke (NINDS) awarded The Leland Stanford Junior University $614,510 on September 1, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to investigate seizure-induced myelin plasticity as a mechanism of generalized epilepsy progression.

The research tests the hypothesis that seizure-induced myelination in the corpus callosum promotes cortical hypersynchrony and generalized epilepsy progression through oligodendroglial BDNF-to-TRKB signaling. Prior work in a mouse model of progressive generalized epilepsy (SCN8A+/-) demonstrated that repetitive seizures induce myelination primarily in the corpus callosum, and that suppression of myelin plasticity by selective deletion of TRKB receptors from oligodendrocyte precursor cells prevented epilepsy progression. The funded research will examine whether seizure-induced callosal myelin plasticity induces oligodendrocyte precursor cell proliferation and differentiation, and whether this myelination promotes cortical hypersynchrony in multiple forms of epilepsy. Standard therapies targeting neuronal excitability and synaptic transmission are only partially effective in generalized epilepsy, which affects approximately 20 percent of people with epilepsy.

The award period runs from September 1, 2026, through August 31, 2031. Work is performed in Palo Alto, California.

Abstract

Epilepsy, defined by recurrent, unprovoked seizures, affects 1 in 26 people. Generalized epilepsy, which is 20% of all epilepsy, involves seizures that begin in both sides of the brain at once. These seizures have spike wave discharge correlates on electroencephalogram (EEG), in which the spikes reflect neuronal hypersynchrony (excessively correlated firing of neurons, both within and between the bilateral cortices). Severe forms of generalized epilepsy involve seizures that become more frequent over time (epilepsy progression), which is thought to result from hypersynchrony. Standard therapies targeting neuronal excitability and synaptic transmission are only partially effective, leading to gaps in care and early mortality. We discovered that seizure-induced myelin plasticity can promote generalized epilepsy progression (knowles ET AL, nature neuroscience, 2022). Myelin plasticity occurs when repetitive patterns of neuronal activity induce changes in myelin sheath structure. In the healthy brain, myelin plasticity is required for learning and adaptation. However, we found that in a mouse model of progressive generalized epilepsy (SCN8A+/-), repetitive seizures also induce myelination, primarily in the corpus callosum. Suppression of myelin plasticity by selective deletion of trkb receptors from oligodendrocyte precursor cells (opcs) in SCN8A+/- trkb OPC CKO mice prevented epilepsy progression. Seizure-induced myelination through oligodendroglial bdnf-to- trkb signaling (which induces OPC proliferation and differentiation to oligodendrocytes) may thus be a fundamental mechanism in multiple forms of epilepsy. We hypothesize that seizure-induced callosal myelination promotes cortical hypersynchrony and generalized epilepsy progression, through bdnf- induced transcription in opcs. In aim 1, we will test the role of seizure-induced callosal myelin plasticity in cortical hypersynchrony, using innovative brain slice physiology and in vivo calcium imaging approaches. In aim 2, we will use single nucleus RNA sequencing and spatial transcriptomics to determine transcriptional regulation of seizure-induced oligodendrogenesis and epilepsy progression. In aim 3, we will determine whether seizure-induced myelin plasticity promotes epilepsy progression in a second genetic model of severe generalized epilepsy, GABRB3+/D120N, using MRI myelin mapping and conditional, inducible deletion of trkb receptors from opcs. This work will establish myelin plasticity as a novel pathogenic mechanism in severe generalized epilepsy, opening new avenues for therapeutic intervention.