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Updated: Aug 26, 2026
A Behavioral Screen for Heat-Induced Seizures in Mouse Models of Epilepsy
Published on: July 12, 2021
Mitochondrial oxidative stress and increased seizure susceptibility in Sod2(-/+) mice
1Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Abstract:
Epileptic seizures can occur as a result of mitochondrial dysfunction. Mitochondria have vital functions such as energy generation, control of cell death, neurotransmitter synthesis, and free radical production. Which of these critical mitochondrial functions contributes to epileptic seizures is unknown. We demonstrate here that a subset of mice with partial deficiency of the mitochondrial superoxide dismutase (Sod2(-/+)) show increased incidence of spontaneous and handling-induced seizures that correlates with chronic mitochondrial oxidative stress (increased aconitase inactivation and 8-hydroxy-2'-deoxyguanosine formation in mitochondria) and diminished mitochondrial oxygen utilization. Before the age at which spontaneous seizures appear in a subset of the mice, Sod2(-/+) mice demonstrated increased susceptibility to behavioral seizures, mitochondrial aconitase inactivation, and neurodegeneration induced by the administration of kainate. These data suggest that chronic mitochondrial oxidative stress initiated by superoxide (O(2)(.-)) radicals is sufficient to increase seizure susceptibility due to aging, environmental stimulation, or excitotoxin administration. Sod2(-/+) mice showed an age-related decrease in the expression of glial glutamate transporters (GLT-1 and GLAST), suggesting that oxidant-induced inhibition of glutamate transport may play a mechanistic role in rendering some Sod2(-/+) mice susceptible to seizures. In summary, mitochondrial oxidative stress and resultant dysfunction may be an important mechanism underlying certain seizure disorders.
Insights
Mitochondrial dysfunction, specifically oxidative stress from superoxide radicals, increases seizure susceptibility in mice. This dysfunction impairs energy production and glutamate transport, contributing to epilepsy.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Epilepsy Research
Background:
- Mitochondria are crucial for cellular functions including energy production and neurotransmitter synthesis.
- Mitochondrial dysfunction is implicated in epileptic seizures, but the specific mechanisms remain unclear.
- Superoxide radicals are a key byproduct of mitochondrial metabolism.
Purpose of the Study:
- To investigate the contribution of mitochondrial dysfunction, particularly oxidative stress, to epileptic seizures.
- To identify which mitochondrial functions, when impaired, lead to seizure susceptibility.
Main Methods:
- Utilized a mouse model with partial deficiency of mitochondrial superoxide dismutase (Sod2(-/+)).
- Assessed seizure incidence, mitochondrial oxidative stress markers (aconitase inactivation, 8-hydroxy-2'-deoxyguanosine), oxygen utilization, and glial glutamate transporter expression (GLT-1, GLAST).
- Administered kainate to evaluate seizure susceptibility and neurodegeneration in Sod2(-/+) mice.
Main Results:
- Sod2(-/+) mice exhibited increased spontaneous and handling-induced seizures, correlating with mitochondrial oxidative stress and reduced oxygen utilization.
- Younger Sod2(-/+) mice showed heightened susceptibility to kainate-induced seizures, neurodegeneration, and mitochondrial dysfunction.
- An age-related decrease in glial glutamate transporters (GLT-1, GLAST) was observed in Sod2(-/+) mice.
Conclusions:
- Chronic mitochondrial oxidative stress from superoxide radicals is sufficient to increase seizure susceptibility.
- Impaired mitochondrial function and reduced glutamate transport may be key mechanisms in age- and stimulus-induced seizures.
- Mitochondrial dysfunction represents a significant underlying factor in certain seizure disorders.
