# Maladaptive Myelination in Pediatric Epilepsy

> **NIH NIH K08** · STANFORD UNIVERSITY · 2021 · $194,399

## Abstract

Project Summary / Abstract
Absence seizures occur in pediatric generalized epilepsy and involve excessive synchrony of the
thalamocortical neural network. An unexplored possibility is that aberrant activity-dependent myelination
contributes to absence seizure progression by promoting network synchrony. A recent discovery is that
neuronal activity drives myelin plasticity (changes in myelin structure) in vivo. Myelination, in turn, is a critical
determinant of neuronal network synchrony and function. Activity-regulated formation of new myelin requires
Brain Derived Neurotrophic Factor (BDNF) signaling through its receptor, TrkB, on oligodendrocyte precursor
cells (OPCs). Pathological seizure activity may also induce changes in myelin structure, which in turn could
contribute to network dysfunction. This proposal investigates the relationship between absence seizures and
activity-dependent myelin plasticity. Preliminary data indicate that absence seizures are associated with
abnormally increased myelination in two rodent models with spontaneous absence seizures: Wag/Rij rats (a
widely used inbred rat strain) and Scn8a+/mut mice. These mice have a loss of function mutation in SCN8A,
similar to children with generalized epilepsy due to loss of function in SCN8A. Both models exhibit increased
OPCs and myelin sheath thickness in the anterior corpus callosum. Preventing seizures with ethosuximide
prevented the increased callosal myelination, indicating that seizures are required. My hypothesis is that
seizure-induced aberrant myelination facilitates excessive synchrony and contributes to seizure
burden. In Aim 1, the nature and extent of abnormal myelination in the thalamocortical network will be
investigated using magnetization transfer and diffusion-based magnetic resonance imaging of Scn8a+/mut mice.
Measurements will be validated by the gold standard method of quantifying myelination, electron microscopy.
Aim 2 will determine the role of activity-dependent myelination in thalamocortical hyper-synchrony underlying
absence seizures. This will be accomplished by conditionally deleting the TrkB receptor from OPCs in
Scn8a+/mut mice specifically during the period of seizure initiation and progression, using a novel mouse line
(Scn8a+/mut; trkB fl/fl; PDGFR::Cre). Indices of network synchrony will be measured in acute thalamic slices
from Scn8a+/mut mice with or without normal activity-dependent myelination. Aim 3 will determine whether
myelin plasticity contributes to seizure burden, by genetically blocking activity-dependent myelination as in Aim
2, and quantifying seizures with EEG. Thus, the proposed studies will use innovative methods to elucidate a
novel and potentially paradigm-shifting pathological mechanism in epilepsy, with implications for new
therapeutic strategies.

## Key facts

- **NIH application ID:** 10301944
- **Project number:** 1K08NS119800-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** JULIET KLASING KNOWLES
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $194,399
- **Award type:** 1
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10301944

## Citation

> US National Institutes of Health, RePORTER application 10301944, Maladaptive Myelination in Pediatric Epilepsy (1K08NS119800-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10301944. Licensed CC0.

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