# Demyelination is coupled to neuronal hyperexcitability leading to seizures

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2021 · $331,645

## Abstract

PROJECT SUMMARY
Multiple sclerosis (MS) patients are three to six times more likely to develop epilepsy compared to the rest of the
population. However, while this groups suffers greater morbidity, the pathophysiology of MS-associated seizures
is unknown. Our long-term goal is to identify mechanisms linking demyelination to neuronal hyperexcitability
and neurodegeneration. The objective in this application is to define the processes by which demyelination itself
causes cellular, molecular and circuit changes increasing neuronal excitability. Our central hypothesis is that
demyelination is coupled to elevated excitability, loss of parvalbumin (PV)+ interneurons, and dysfunction of
astrocyte metabolism/transport. This hypothesis is based on our recently published work demonstrating marked
changes in electroencephalography (EEG) and spontaneous seizures in mice fed 0.2% cuprizone diet (CPZ) over
a period of 9-12 weeks; and subsequent immunohistochemistry revealed loss of PV+ neurons in the hippocampal
CA1 subregion together with widespread gliosis and changes in astrocytic aquaporin-4 (AQP4) expression com-
pared to mice on a normal diet. The rationale for the proposed research is that detailed spatiotemporal moni-
toring of EEG activity with multielectrode arrays (MEA) in CPZ-treated mice will allow identification of the locus
and timing of seizure initiation during chronic demyelination, and this will direct the probe of excitatory/inhib-
itory neurotransmission and cellular/molecular changes by immunohistochemical and electrophysiological tech-
niques. Based on new preliminary data, the central hypothesis will be tested by pursuing three specific aims: 1)
Define the spatial and temporal generation of chronic demyelination-associated seizures; 2) Evaluate the role of
GABAergic neurons with an emphasis of PV neurons in the generation of chronic demyelination-induced sei-
zures; 3) Evaluate the role of astrocytes in regional seizure susceptibility during chronic demyelination. Novel
electrophysiological and transgenic approaches together with direct comparison to human tissue from patients
with MS with and without seizures will elucidate demyelination-associated cellular and molecular changes that
lead to seizure susceptibility. The proposed research is significant, because it will advance fundamental
knowledge of glial-neuronal interactions in the brain while providing new and rational strategies and treatments
for prevention and treatment of MS-associated seizures.

## Key facts

- **NIH application ID:** 10087976
- **Project number:** 5R01NS111552-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** DEVIN K BINDER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $331,645
- **Award type:** 5
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10087976

## Citation

> US National Institutes of Health, RePORTER application 10087976, Demyelination is coupled to neuronal hyperexcitability leading to seizures (5R01NS111552-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10087976. Licensed CC0.

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