Project Summary The lack of drug effectiveness in refractory epilepsy (~30% of peoplw with epilepsy) implies the existence of additional mechanisms of hyperexcitability and hypersynchrony that current anti-seizure drugs do not target. The long-term goals of our research program are to identify novel molecular targets with disease-modifying effects for the treatment of refractory epilepsy, which may also decrease co-morbidities and increase longevity in those susceptible to SUDEP. In the past decade, inflammation has been found to have a detrimental impact on epilepsy. A minority of studies have focused on peripheral immune responses but have found that severe human and animal refractory epilepsies exhibit a chronic CNS inflammatory state with activation and infiltration of peripheral adaptive immune cells into the brain. However, the relationship between chronic epilepsy and the peripheral adaptive immune system is unknown. The objective of this grant is to determine the role of peripheral adaptive immune response in seizure generation, seizure severity and epileptogenesis. The central hypothesis is that epileptic seizures cause activation of the peripheral adaptive immune response and that seizure-induced peripheral adaptive immune responses contribute to worsening seizures/epilepsy. Our rationale is that delineating the nature of the relationship between chronic epilepsy and the peripheral adaptive immune system will offer new research avenues and therapeutic opportunities. Our specific aims will test the following hypotheses: (Aim 1) Spontaneous recurrent seizures in chronic epilepsy alter the peripheral immune response resulting in brain infiltration of peripheral immune cells; and (Aim 2) Peripheral adaptive immune cells contribute to the age-dependent worsening of seizure severity in epileptic mice. Upon conclusion, we will understand seizures in the setting of peripheral inflammation. The proposed research is innovative because we investigate the effect of spontaneous recurrent seizures on peripheral inflammatory signaling and vice versa in a developmental model of temporal lobe epilepsy, a heretofore-unexamined process.