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Updated: May 27, 2026
A Behavioral Screen for Heat-Induced Seizures in Mouse Models of Epilepsy
Published on: July 12, 2021
Phenotypic differences between fast and slow methionine sulfoximine-inbred mice: seizures, anxiety, and glutamine
Arnaud Boissonnet1, Tobias Hévor, Jean-François Cloix
1Laboratoire de Neurobiologie, Rue de Chartres, Université d'Orléans, 45067 Orléans CEDEX 2, France.
Abstract:
Seizures induced by the convulsant methionine sulfoximine (MSO) resemble human "grand mal" epilepsy, and brain glutamine synthetase is inhibited. We recently selected two inbred lines of mice: sensitive to MSO (MSO-Fast) and resistant (MSO-Slow). In the present study, the selection pressure was increased and consanguinity established. To gain insight into the mechanisms of epileptogenesis, we studied the behaviour of MSO-Fast and MSO-Slow mice based on their responses to various convulsants and anticonvulsants, and also the kinetics of glutamine synthetase. The results show that increasing the number of generations of sib-crossings resulted in an increase in the differences between MSO-Fast and MSO-Slow mice. The dose-response curve of MSO-dependent seizures demonstrated that the MSO-Slow mice were highly insensitive to MSO-dependent seizures compared with MSO-Fast inbred mice that were highly sensitivity. The MSO-Slow were resistant to convulsions induced by various convulsants having different mechanisms of action, whereas those in the MSO-Fast line were more sensitive to kainic acid-induced seizures. These data, in addition to the effects of anticonvulsant, strongly suggest that glutamatergic pathways are most likely involved in MSO-dependent seizures, rather than GABAergic ones. This hypothesis is corroborated by the glutamine synthetase activity, which is more elevated in the MSO-Slow line. Behaviour tests showed that MSO-Slow were less anxious than MSO-Fast. Collectively, these results showed that glutamatergic pathways could be involved in the epileptogenic action of MSO, which may be related to the glutamate/glutamine cycle in the brain.
Insights
Methionine sulfoximine (MSO)-induced seizures, mimicking epilepsy, were studied in fast-sensitive and slow-resistant mouse lines. MSO-Slow mice showed resistance to seizures, suggesting altered glutamatergic pathways and reduced anxiety.
Area of Science:
- Neuroscience
- Epilepsy Research
- Biochemistry
Background:
- Methionine sulfoximine (MSO) induces seizures similar to human epilepsy by inhibiting brain glutamine synthetase.
- Two inbred mouse lines, MSO-Fast (sensitive) and MSO-Slow (resistant), were previously selected based on MSO response.
- Further selection and inbreeding intensified the differences between these lines.
Purpose of the Study:
- To investigate the mechanisms of epileptogenesis by comparing MSO-Fast and MSO-Slow mice.
- To analyze behavioral responses to various convulsants and anticonvulsants.
- To examine glutamine synthetase kinetics and anxiety levels in relation to MSO sensitivity.
Main Methods:
- Increased selection pressure and consanguinity in MSO-Fast and MSO-Slow mouse lines.
- Dose-response studies using MSO and other convulsants (e.g., kainic acid).
- Assessment of anticonvulsant effects and measurement of glutamine synthetase activity.
- Behavioral tests to evaluate anxiety levels.
Main Results:
- Enhanced genetic divergence between MSO-Fast and MSO-Slow lines after further generations of selective breeding.
- MSO-Slow mice exhibited significant resistance to MSO-induced seizures and convulsions from various agents compared to MSO-Fast mice.
- MSO-Fast mice showed increased sensitivity to kainic acid-induced seizures.
- Elevated glutamine synthetase activity and reduced anxiety were observed in MSO-Slow mice.
- Anticonvulsant data suggested involvement of glutamatergic rather than GABAergic pathways.
Conclusions:
- Glutamatergic pathways are strongly implicated in the epileptogenic action of MSO.
- The glutamate/glutamine cycle in the brain may play a crucial role in MSO-induced seizures.
- Genetic factors influencing glutamine synthetase activity and anxiety levels contribute to MSO sensitivity/resistance.
