# Multiscale modeling and large-scale recordings of trauma-induced epileptogenesis

> **NIH NIH R01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2020 · $613,864

## Abstract

Project Summary/Abstract
The goal of this research is to understand why cerebral cortical trauma often leads to seizures and to propose
interventions that may reduce or prevent trauma-induced epileptogenesis. Within 24 hours following head
injury, up to 80% of patients with penetrating wounds display clinical seizures. Such acute seizures often
initiate epileptogenesis―the subthreshold processes that lead to spontaneous, recurring seizures and
ultimately to epilepsy. The primary hypotheses of this project are: 1) Trauma-related chronic blockade of
activity activates homeostatic plasticity mechanisms that upregulate depolarizing influences (such as excitatory
intrinsic and synaptic conductances) and downregulate hyperpolarizing ones (such as inhibitory
conductances); in traumatized cortex, this may create an unstable balance of excitation and inhibition that
leads to paroxysmal seizures; 2) The effect of the pathological homeostatic changes is age dependent with
older animals being more prone to seizures; 3) External interventions designed to prevent decrease of activity
after trauma reduce the likelihood of epileptic seizures. Importantly, rather than focus on the ways to treat
epilepsies after epileptogenesis is complete, this proposal aims to develop new techniques that can interfere
with a process of epileptogenesis itself. Following past experiments with cats in the Timofeev laboratory, a
well-established undercut model of cortical deafferenation will be used to induce seizures in mice experiments
in vivo and in vitro. Measurement will be performed over the medium-term (days) and long-term (weeks).
Interventions will be explored that can prevent epileptogenesis using pharmocogenetic stimulation to block
homeostatic changes. In vivo electrophysiological semichronic and chronic experiments will be performed at
Laval University (Canada). In vitro experiments from deafferented cortical slices will be conducted at Laval
University and UCSD. Necessary data on the astrocyte properties will be provided by the collaborators (Dr.
Nedergaard, Univ of Rochester). Experimental data will be analyzed at The Salk Institute and UCSD and will
be incorporated into large-scale network models of the neocortex, implementing subcellular, circuit and
network level properties, at the Salk Institute and UCSD. The computational models allow the interplay
between all of the changes that occur in the cortex in vivo during epileptogenesis to be simulated to identify the
critical mechanisms and to make predictions for intervention strategies that could prevent epileptogenesis.

## Key facts

- **NIH application ID:** 9959525
- **Project number:** 5R01NS104368-03
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** TERRENCE J SEJNOWSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $613,864
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959525

## Citation

> US National Institutes of Health, RePORTER application 9959525, Multiscale modeling and large-scale recordings of trauma-induced epileptogenesis (5R01NS104368-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9959525. Licensed CC0.

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