DESCRIPTION (provided by applicant): Epilepsy is a devastating neurological disorder that is nearly incurable, requiring the continuous presence of therapeutics. Moreover, about one-third of patients with epilepsy are refractory to available medications. Therefore, there is a pressing need to understand epileptogenesis, the pathological process that transforms a normal brain into an epileptic brain. In acquired epilepsy, epileptogenesis typically begins following brain injury, and is increasingly recognized to involve brain inflammation. Microglia are the primary immune cells in the brain. However, the role of microglia in epileptogenesis remains poorly understood. Our preliminary study revealed that double-stranded DNA (dsDNA) can trigger a robust innate immune response in microglia. Moreover, we found that inactivation of ULK1, a kinase in the autophagy pathway, promotes the innate immune response to dsDNA. Given that neurodegeneration is strongly associated with an early onset of epileptogenesis in most acquired epilepsy models and is also observed in the brains of epileptic patients, we postulated: 1) dsDNA released from dead neurons could be the trigger that induces the innate immune response in microglia, which in turn promotes epileptogenesis; and 2) ULK1 is a key regulator involved in terminating the innate immune response to prevent an excessive inflammatory process. Here we propose to delineate the pathway by which ULK1 regulates the innate immune response of microglia to dsDNA from degenerated neurons. We will also examine the effect of inactivation of ULK1 on the innate immune response in microglia and epileptogenesis in the pilocarpine mouse model. Finally, we will employ a recently developed chemogenetic strategy to probe the role of microglia in epileptogenesis. Results from this study could lead to new strategies to prevent excessive inflammation in microglia, therefore minimizing the epileptogenic effect.

PUBLIC HEALTH RELEVANCE: The goal of this proposal is to clarify the role of microglia in epileptogenesis. Epilepsy is a devastating disorder that remains nearly unpreventable. Results from this study could lead to new strategies to prevent excessive inflammation in microglia so as to minimize the epileptogenic effect