PROJECT SUMMARY Febrile seizures are the most common form of childhood seizures. They affect 2-5% of children between the ages of 6 and 60 months. They occur with a rise in body temperature that is often associated with a fever, though the underlying mechanisms are not fully understood. In a subset of children with febrile seizure, seizures and convulsions are prolonged and are referred to as febrile status epilepticus (fSE). Some children that experience fSE go on to develop epilepsy in childhood or adulthood making childhood fSE a risk factor for subsequently developing epilepsy. Although the underlying mechanisms governing status epilepticus and epilepsy are known to emanate from neuronal dysfunction, compelling research in recent years suggest contributions from inflammation, broadly characterized, in fSE. This is evidenced by increased inflammatory mediators in fSE and reduced SE with broad-acting anti-inflammatory drugs. However, inflammation, can be generated by resident cells of the brain such as microglia and astrocytes as well as peripheral immune cells that can release inflammatory mediators outside the brain to alter neuronal function. Current research has thus far failed to delineate cell-specific contributions to inflammation in the context of fSE. In this project, we have begun to determine distinct contributions from microglia, the primary resident immune cell of the brain, in fSE. Given broadly detrimental roles for inflammation in fSE, it has been assumed that microglia, as inflammation-competent cells, promote fSE. Contrary to this assumption, our preliminary experimental results in both chemical- and hyperthermia- induced SE, indicate that microglia actually play beneficial roles in reducing SE severity in mouse models. Moreover, we have identified the microglial-specific P2Y12R as a candidate regulator of microglial beneficial contributions during experimental SE. Therefore, using well-established microglial elimination approaches, we will now: (1) test for general microglial roles in hyperthermia-induced SE and determine whether microglial regulate the neuroinflammatory environment in SE (Aim 1); (2) test for specific microglial P2Y12R roles in regulating microglial beneficial contributions to controlling hyperthermia-induced SE (Aim 2); and (3) determine microglial P2Y12R roles in the progression to temporal lobe epilepsy (TLE) using a novel mouse model follow early life exposure to hyperthermia-induced SE (Aim 3). This project is a first to adequately clarify microglial contributions in a mouse model of fSE as a pre-clinical model. This work will provide a framework for targeting microglia as a novel approach to ameliorate SE in general and fSE in particular.

PROJECT NARRATIVE. Microglia are brain-resident immune cells whose role in prolonged seizures (otherwise known as status epilepticus) during development is not known. Emerging research in neurodegenerative diseases suggest that targeting microglia is a promising approach to treat such diseases. This proposal investigates the possibility of manipulating microglia, with a special focus on one of its principal receptors, in developing mice as a pre-clinical model for seizure management in pediatric seizures and epilepsy development.