Investigating the role of the innate immune system, oxidative stress, and cell death in a Drosophila model of epilepsy

Epilepsy is a neurological disorder characterized by seizures that affects nearly 1% of the US population. About one-third of patients do not respond to currently available anti-epileptic medications, thus underscoring the need to develop new treatments. Our lab has previously identified that mutations in the prickle (pk) gene cause seizures in flies and humans. We used Drosophila to assess the underlying disease mechanisms in pk mutants that lead to epilepsy and demonstrated that pk mutant brains experience an aggravated immune response, oxidative stress, and cell death. We also showed that, similar to humans, seizures in fly pk mutants get worse with age. Using a combination of genetic, microscopy, and behavioral tools, we were able to demonstrate that suppression of the brain immune system can suppress both the cell death and seizures in pk mutants, thus providing the first genetic evidence for the involvement of the brain immune response in exacerbating seizures in a Drosophila model of human epilepsy. We showed that by mitigating excessive oxidative stress in the nervous system of pk mutants, we were able to suppress seizure activity, thus suggesting that oxidative stress in combination with brain immune response is involved in exacerbating the seizures in pk mutants. Together, these data propose a novel pathway involved in seizure exacerbation which will aid in identifying alternative and effective treatment modalities to reduce the severity of this disease.