Inflammation May Drive Rare Epileptic Syndrome

Published in the Cornell Chronicle 

An overactive immune response in the brain may play a role in Dravet syndrome, a rare and severe genetic epilepsy caused by mutations in the gene SCN1A and which typically begins in infancy. Children with the condition experience frequent seizures that are often difficult to control with medication, and may also face developmental, cognitive, and behavioral challenges. Until now, most research has focused on how mutations in the SCN1A gene disrupt electrical signaling in the brain, however, a recent study focused elsewhere.

“Rather than being a disorder only involving abnormal electrical signaling, the disease may also involve a self-sustaining immune response triggered by DNA released from stressed neurons,” said study author Dr. Li Gan. “This response may be triggered by an inflammatory pathway called cGAS-STING-interferon (IFN-I) which may help drive and sustain the disease.”

The team found that the brain’s IFN-I system is triggered when overactive neurons become stressed and release fragments of DNA. The DNA then activates immune cells called microglia, which launch an inflammatory response, particularly in the hippocampus, a brain region implicated in seizures. That inflammation, in turn, can make the brain even more susceptible to seizures.

To test how the pathway may contribute to seizures, the team genetically reduced cGAS activity in a mouse model of Dravet syndrome. Mice with reduced cGAS activity experienced fewer severe seizures, and showed lower levels of abnormal brain activity. They also treated Dravet syndrome mice with an experimental drug, which inhibits the cGAS pathway.

The treatment reduced inflammatory changes in both microglia and astrocytes (another type of brain support cell involved in neurological disease). The findings suggest that the pathway acts as a critical link between neuronal dysfunction and neuroinflammation. By interrupting this signaling pathway, the researchers were able to calm the brain’s immune response and reduce seizure susceptibility.

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