Status epilepticus (SE) is a neurological emergency that afflicts 120-160,000 Americans each year, which can cause brain damage and contribute to mortality. Approximately one third of patients in SE are refractory to current therapies. We will investigate the role of AMPA receptor plasticity in benzodiazepine resistant SE using genetically modified mice, advanced imaging and electrophysiology; and we will test a novel therapy. In Aim 1, we propose to test whether a single seizure and SE enhance AMPAR mediated synaptic transmission in activated CA1 pyramidal neurons and the entorhinal cortex using patch clamp electrophysiology and biochemical techniques. The experiments in Aim 2 test the role of GluA1 plasticity in seizure spread and duration using global and conditional knockout mice. In Aim 3, we test the efficacy of IEM 1460, a drug that targets modified AMPA receptors, in terminating SE. This project will provide novel insights into the mechanisms of SE initiation by repeated seizures. It will define the role of GluA1 subunit plasticity in seizure spread during benzodiazepine refractory SE; and provide the neurobiological basis for the development and use of drugs targeting calcium permeable AMPA receptors for terminating SE.