PROJECT SUMMARY/ABSTRACT Patients in status epilepticus present with continuous seizures that are life-threatening without successful and emergent seizure termination. Despite the fact that current therapies fail to stop seizures in 20% of patients, physicians have relied on essentially the same treatment strategy for SE for almost 50 years: anti-seizure drugs, such as benzodiazepines and other anti-convulsive agents. When treatment fails, patients enter refractory SE for which the mortality rate can reach 60%. Not only is SE a medical emergency with a high mortality rate, survivors are often left with irreversible and lasting brain damage. After a single episode of SE, almost half of patients will develop spontaneous recurrent seizures and temporal lobe epilepsy. Further, psychiatric comorbidities, such as anxiety and depression, are highly associated with the chronic epileptic state. Therefore, to reduce both mortality and morbidity, it is imperative to elucidate the underlying mechanisms that drive the severity and consequences of SE. As a life-threatening stressor, SE results in robust activation of the hypothalamic-pituitary-adrenal axis and stress hormone (i.e., glucocorticoid) release. Multiple lines of evidence suggest that glucocorticoids can increase neuronal excitability under basal conditions and exacerbate excitotoxic injury under pathological conditions. In fact, we have shown that giving exogenous glucocorticoids to epileptic rodents makes seizures worse. However, exactly which brain regions or cell types mediate this effect is unknown. Here, I hypothesize that glucocorticoids worsen status epilepticus severity by increasing the excitability of hippocampal dentate granule cells. In the seizure-free brain, dentate granule cells limit or “gate” the amount of excitatory activity that can enter the hippocampus, thereby preventing the propagation of seizures. Dentate granule cells are rich in glucocorticoid receptor expression; therefore, if glucocorticoids increase dentate granule cell excitability, this gating function is likely to fail during SE, allowing seizures to grow and spread. To test my hypothesis, I have optimized a viral-mediated strategy to selectively delete glucocorticoid receptors from hippocampal dentate granule cells prior to pilocarpine-induced SE. Using this approach, I will determine whether glucocorticoid receptor deletion 1) decreases status epilepticus severity (Aim 1) and/or 2) decreases dentate granule cell excitability (Aim 2). These studies will reveal whether glucocorticoid receptor-mediated failure of the dentate gate plays a role in exacerbating status epilepticus-induced injury to the hippocampus.