# MOLECULAR DISSECTION OF SEIZURE MICROENVIRONMENT IN MALIGNANT GLIOMA

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $632,130

## Abstract

Glioblastoma cells trigger pharmacoresistant seizures that may promote tumor growth and diminish the quality
of remaining life. To define the relationship between growth of glial tumors and their neuronal
microenvironment, and to identify genomic biomarkers and mechanisms that may point to better prognosis and
treatment of drug resistant epilepsy in brain cancer, we are analyzing a new generation of genetically defined
CRISPR/in utero electroporation inborn glioblastoma (GBM) tumor models engineered in mice. The molecular
pathophysiology of glioblastoma cells and surrounding neurons and untransformed astrocytes will be
compared at serial stages of tumor development in three genetic mouse strains: wild type, seizure prone, and
seizure resistant. Preliminary data reveal that epileptiform EEG spiking is a very early and reliable preclinical
signature of GBM expansion preceding other neurological deficits in these mice, followed by rapidly
progressive seizures and death within weeks. Transcriptomic analysis of cortical astrocytes reveals the
expansion of a subgroup enriched in pro-synaptogenic genes that may drive hyperexcitability, a novel
mechanism of epileptogenesis. In Specific Aim 1 we will systematically define the earliest appearance of
cortical hyperexcitability in wild type mice with a prototypical GBM and correlate its progression with in vivo and
neuropathological imaging of invasive tumor cell location, in vitro electrophysiology, and molecular markers of
key epilepsy pathogenic cascades in peritumoral neurons, including impaired glutamate reuptake, altered
GABA gated-chloride gradients, and synaptic densities. In Specific Aim 2 we will correlate these findings with
detailed FACS-sorted transcriptomic profiles of both transformed and wild type astrocytes in the peritumoral
region to test the novel hypothesis that peritumoral hyperexcitability is driven in part by astrocytic subtypes that
disrupt synaptic E/I homeostasis. In Specific Aim 3, we will use this benchmark approach in WT brain to
compare growth, electrophysiological and molecular pathological profiles of the same tumor generated in a
hyperexcitable brain bearing a single gene deletion (Kcna1) that dramatically lowers the threshold for seizures
and shortens lifespan, and in a monogenic deletion strain (MapT/tau) that raises cortical seizure threshold and
prolongs life, in order to examine the contribution of host neuronal excitability to tumor expansion. Our
approach sets the stage to broadly explore the developmental biology of personalized tumor/host interactions
in mice engineered with novel human tumor mutations in specified glial cell lineages.

## Key facts

- **NIH application ID:** 10062889
- **Project number:** 5R01CA223388-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Benjamin Deneen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $632,130
- **Award type:** 5
- **Project period:** 2017-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062889

## Citation

> US National Institutes of Health, RePORTER application 10062889, MOLECULAR DISSECTION OF SEIZURE MICROENVIRONMENT IN MALIGNANT GLIOMA (5R01CA223388-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10062889. Licensed CC0.

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