Understanding epilepsy through a new mouse model

Epilepsy affects most individuals with tuberous sclerosis complex, or TSC, yet the link between small cortical abnormalities and seizure generation is not fully understood. In a new study published in Frontiers in Molecular Neuroscience [1], researchers in Dr. Candi LaSarge's lab at Cincinnati Children’s and the University of Cincinnati introduced a mouse model designed to answer a central question: Is a small, localized disruption in the frontal cortex enough to trigger epilepsy and related behavioral changes? The results show that it is, and they also demonstrate how automated behavioral tracking can support this type of research.

Modeling tuberous sclerosis and focal epilepsy

TSC is caused by mutations in the genes Tsc1 or Tsc2, which alter the mTOR pathway and affect cell growth. Many patients develop focal cortical lesions, known as tubers, that are strongly associated with seizures. However, it has been unclear whether such focal abnormalities alone are sufficient to create epileptic networks, or whether more widespread developmental changes are required.

To test this directly, the research team deleted Tsc2 in a very small area of the frontal cortex shortly after birth. This approach allowed them to isolate the effects of a discrete lesion without disrupting the rest of the brain.

The impact of a targeted Tsc2 deletion

Even though the lesion was small, its impact was significant.

• All mice with the focal Tsc2 deletion developed spontaneous seizures during EEG monitoring.
• The affected neurons were enlarged and showed hyperactivation of the mTOR pathway.
• Surrounding cortical tissue contained fewer inhibitory interneurons and showed increased microglial activation.

Connecting cellular changes to behavior

In addition to physiological outcomes, the team examined how the focal lesion influenced natural exploration. Behavior provides an essential complement to cellular and EEG data because it reflects how neural disruptions affect real-world function. Mice were placed in an open field arena for thirty minutes while their movement was tracked with EthoVision. This allowed the team to quantify locomotion and spatial preferences with high accuracy.

The results showed a consistent pattern. Mice with the Tsc2 deletion explored the arena but avoided the center area. They displayed high thigmotaxic behavior, meaning they remained close to the walls, which is often interpreted as increased anxiety. Importantly, the groups did not differ in total distance traveled. This means the shift in exploration strategy was not caused by reduced mobility but by a change in how the animals chose to explore the space.



Copyright © 2025 McCoy, Dusing, Jerow, Winstel, Zhan, Rogers, Wesley, Otten, Danzer and LaSarge

How EthoVision contributed

EthoVision supported the study by providing reliable, high resolution movement data in a simple and unobtrusive way. The software allowed the researchers to quantify center time, thigmotaxis, and locomotor activity without manual scoring. These measures helped reveal the behavioral effects of the focal lesion and supported the broader conclusion that local cortical disruptions can influence both seizures and behavior.

Automated tracking is especially helpful in TSC and epilepsy research. Many behavioral changes are subtle, and consistent quantification is important when linking behavior to cellular and network level findings.

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A model that supports future research

This focal TSC model brings together several important features of the disorder. It produces seizures, altered inhibitory circuits, neuroinflammation, and changes in exploration. Because the lesion is small and well defined, the model can help researchers investigate how specific cortical disruptions lead to epileptic activity and behavioral consequences.

By combining EEG, histology, and automated behavioral tracking, the researchers created a comprehensive picture of how focal pathology affects the whole animal. This integrated approach will support future studies on epileptogenesis, circuit dysfunction, and potential therapeutic interventions.

References

[1] McCoy C, Dusing M, Jerow LG, Winstel GC, Zhan F, Rogers JL, Wesley M, Otten JB, Danzer SC and LaSarge CL (2025). Focal postnataldeletionof Tsc2 causes epilepsy. Front.Mol.Neurosci. 18:1686023. https://doi.org/10.3389/fnmol.2025.1686023.