# Subcortical nodes within epileptic network control the cortical disfacilitation to prompt seizure onset in IGE mouse model

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $345,625

## Abstract

Seizures affect more than 3 million people in US, creating tremendous burdens to patients and their
families/communities. Some intractable seizures with genetic causes (idiopathic generalized epilepsy, IGE) are
resistant to conventional antiepileptic drugs. Although major progress has been made regarding mechanisms
of acquired epilepsy, the causes for IGE remain elusive. We have not completely understood how the balance
between synaptic/neuron excitation and inhibition is dynamically impaired under some conditions for IGE
models. Moreover, functional MRI studies on seizures undeniably indicate that whole-brain networks (cortical
and remote subcortical nodes) are involved during epileptic activity, suggesting that seizures are the emerging
consequence of whole-brain epileptic network activity at the microscopic, mesoscopic, and macroscopic
scales. However, it still remains challenging for clinical researchers to forecast how epileptic network nodes
interact at network levels to generate the high-voltage spike-wave discharges (SWDs) during seizures.
Specifically, no previous studies have ever focused on exactly how seizure onset and epileptic activity in IGE
models are initiated through the interaction between epileptic network nodes at the network level, why seizures
in human epileptic patients mostly occur during sleep-wake transition/quiet-awake period, and why seizure-
presage conditions such as emotional prodromic aura phenomena can cause seizures in both acquired
epilepsy and IGE patients. Thus, we hypothesize that subcortical nodes within epileptic network nodes,
specifically anterior hypothalamus nucleus and medial amygdala, control cortical disfacilitation (neurons are
hyperpolarized due to the absence of excitatory synaptic activity(Contreras et al., 1996; Timofeev et al., 1996;
2001)) during sleep-wake transition/quiet-awake period and other emotional prodromic auras. The resulting
cortical disfacilitation prompts high-voltage slow-wave oscillations (SWOs), which hemostatically potentiate
synaptic excitation (not inhibition) of epileptic neuron ensembles/engrams in the cortex. Eventually, these chain
events lead to cortical neuron synchronous firing within epileptic network to trigger seizure onset and SWDs. It
is the preceding cortical disfacilitation state in our IGE mouse models (present during sleep-wake
transition/quiet-awake period and some emotion prodromic aura states) that consequently controls seizure
onset and epileptic activity, which offers the network mechanism for IGE models. This proposal will use
transgenic mice with neuron GFP expression (driven by activity dependent c-Fos promoter) to identify the
epileptic network nodes in both cortex and subcortical structures in heterozygous Gabrg2Q390X or Gabra1A322D
KI mice and determine whether the anterior hypothalamus and medial amygdala can cause cortical
disfacilitation with optogenetic stimulation in vivo in these KI mice(neuron expressing ChR2/halorhodopsin
driven by c-Fos ...

## Key facts

- **NIH application ID:** 9988524
- **Project number:** 5R01NS107424-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Chengwen Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $345,625
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988524

## Citation

> US National Institutes of Health, RePORTER application 9988524, Subcortical nodes within epileptic network control the cortical disfacilitation to prompt seizure onset in IGE mouse model (5R01NS107424-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9988524. Licensed CC0.

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