# Evaluating astrocyte loss after traumatic brain injury in initiation of post-traumatic epilepsy

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2021 · $414,927

## Abstract

Project Summary
After years of assuming that neurological diseases are caused by direct damage to neurons, we now know that
impaired astrocyte physiology and function precedes and is essential for the progression of many of these
diseases. This revelation hints toward the reason why anti-epileptic drugs that exclusively target neurons do
not prevent the development of epilepsy after traumatic brain injury (TBI), the largest group of acquired
epilepsies. For more than a decade, data have accumulated showing that astrocytes become reactive and lose
their homeostatic functions indispensable for normal neuronal operation in epilepsy patients and animal
models. Yet, a direct causal link between astrocyte dysfunction and post-traumatic epilepsy (PTE) has not been
established beyond the fact TBI triggers astrogliosis. This may be in part due to the complexity of TBI, which
induces many pathobiological mechanisms in parallel. Astrogliosis has mostly been studied in focal TBI, where
layers of different types of reactive astrocytes surround a site of primary brain damage. Yet, this injury type
presents in isolation in less than 10% of TBI patients and induces additional mechanisms that could trigger
seizures, limiting our ability to determine if a causal relationship between astrocyte dysfunction and the
development of PTE exists. Current PTE models are induced by focal TBI, but the vast majority of human TBIs
include diffuse or concussive injury induced by rapid acceleration/deceleration of the brain tissue. Even
patients who incur a single mild diffuse TBI are at increased risk for the development of PTE. Therefore, a new
PTE mouse model that recapitulated diffuse TBI without focal injury was developed. This new PTE model
induced spontaneous seizures at higher incidence than previous PTE models but with only a subset of cellular
and tissue level changes, markedly reducing complexity of the underlying pathobiology. Data obtained in this
model point to a surprisingly different response of astrocytes to diffuse TBI, suggesting that early loss of
astrocytes may contribute to the development PTE. Yet, the upstream molecular mechanism inducing astrocyte
loss and the downstream physiological consequences on neurons and neighboring astrocytes must be identified
to ultimately find targets for interrupting the progression of TBI to PTE. This proposal aims to determine the
primary cause for astrocyte loss using modified Folch extraction and fractionation techniques to narrow down
the list of candidates. It further tests the hypothesis that astrocyte loss causes neurons and close-by astrocytes
to become dysfunctional, initiating the formation of a seizure focus. This hypothesis will be tested using a
combination of imaging, electrophysiology and EEG recordings in PTE mice or after specific ablation of cellular
players. Given that the incidence of TBI has increased over the last decade, PTE as a lifelong complication of
TBI is not only debilitating for those afflicte...

## Key facts

- **NIH application ID:** 10076866
- **Project number:** 5R01NS105807-04
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Stefanie Robel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $414,927
- **Award type:** 5
- **Project period:** 2018-01-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10076866

## Citation

> US National Institutes of Health, RePORTER application 10076866, Evaluating astrocyte loss after traumatic brain injury in initiation of post-traumatic epilepsy (5R01NS105807-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10076866. Licensed CC0.

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