Some brain cells are supposed to act like brakes during seizures. But in a form of epilepsy linked to abnormal brain development, one group of those supposed brakes may instead help a seizure spread. Seizures caused by cortical dysplasia often have a poor outlook even with medicines and surgery, likely because the seizure network is widespread.

Earlier studies focused mainly on the abnormal area itself, rather than remote regions such as the hippocampus. The study found that hippocampal somatostatin-positive interneurons are involved in these seizures and paradoxically help them spread into generalized seizures.

Here, the hippocampus acts like a building’s distant electrical room: a fault outside the original focus can still feed the widespread seizure network and set the whole building into alarm. When the hippocampus was more involved in seizures, those seizures spread across more brain regions in type one disease.

This wider spread was also linked to more relapses after surgery, suggesting the hippocampus may help sustain a harder-to-treat seizure network. When the somatostatin-positive interneurons were inhibited in the rats with cortical dysplasia, seizure generalization was largely abolished: fewer animals developed generalized seizures, and those seizures were shorter.

The opposite happened when these cells were activated: seizures generalized faster and lasted longer. But activation did not change seizure onset, suggesting that these cells mainly help a seizure spread after it begins. Together, the results suggested that dentate-gyrus somatostatin-positive interneurons become increasingly active during generalized seizures and facilitate their spread.

In these rats, this group of brain cells became active as seizures spread, and switching them off sharply reduced generalized seizures. Turning them on had the opposite effect, showing they help drive seizure spread rather than merely accompanying it. In the rats with cortical dysplasia, around thirty-three percent of somatostatin-positive interneurons carried markers associated with both glutamate release and GABA release.

In control rats, those markers showed only minimal overlap in somatostatin-positive interneurons. The results therefore suggested an increased probability that these cells release glutamate in cortical dysplasia, producing a direct activating effect on nearby granule cells.

The hippocampus is far from the visibly abnormal brain area, yet the data suggest that it is a key determinant of the widespread seizure network. Within that overactive hippocampus, increased glutamate release from somatostatin-positive interneurons provides the cellular change linked to the network.

The results provide evidence that somatostatin-positive interneurons in the dentate gyrus are crucial elements driving the large-scale seizure network. The study identifies hippocampal somatostatin-positive interneurons as a potential treatment target for seizures caused by cortical malformations.

That matters for patients because a seizure may be sustained by a widespread network involving hippocampal circuitry, rather than being confined to the visible cortical malformation. Future treatments might need to find and quiet that circuit as well, because hippocampal somatostatin-positive interneurons are a potential therapeutic target in seizures due to cortical malformations.

The study points to a hidden driver of widespread seizures: a remote hippocampal circuit whose normally calming cells can release an activating signal. That could open a new route for understanding and treating seizures that surgery does not fully control.