The issue of what starts and stops individual epileptic seizures is a topic of intense interest and investigation. Brain dynamics can rapidly cycle between a state supporting normal, physiological activity and an epileptic state characterized by uncontrolled and intense, usually oscillatory activity. This is especially the situation for generalized absence epilepsy, in which individual seizures occur suddenly and briefly interrupt behavior for perhaps a few seconds, and then just as suddenly terminate to allow resumption of normal activity. The thalamocortical system is involved in these transitions in absence epilepsy, with the thalamic reticular nucleus and its inhibitory output playing an essential role. It has recently been shown that derangements in excitatory connectivity from cortex or thalamus to the thalamic reticular nucleus can lead to experimental absence seizures. The proposed studies will examine the response dynamics of reticular neurons in a variety of conditions that mimic the beginning, middle and end of seizures. Experiments will involve photostimulation of axons via virally delivered genetically encoded opsins that will allow specific and simultaneous interrogation of thalamic and/or cortical pathways. Using whole cell voltage- and current-clamp recordings from thalamic neurons in brain slices, experiments will determine the patterns of cortical inputs that dynamically switch the thalamic subcircuit into seizure generating mode, and determine how interactions between cortical and thalamic inputs sustain and propagate the seizures. Studies will examine activity dependent changes in synapse efficacy mediated by the metabotropic glutamate receptor mGluR7a, which has been shown to play a role in absence seizure regulation. Finally, experiments will determine the excitatory conditions under which the normally protective interconnections between reticular neurons break down leading to seizure onset. The results of these studies will lead to an understanding of brain dynamics in absence epilepsy and guide development of new therapies. PUBLIC HEALTH RELEVANCE: Patients with epilepsy have the unique challenge of dealing with the unpredictable nature of their seizures. The exact time that each seizure will occur is unknown as is how long each seizure will last. The proposed research will determine the events in the central nervous system that lead up to seizures, especially in childhood absence epilepsy, with the ultimate hope that improved seizure therapies can be developed.