Epilepsy is a major debilitating disorder of the central nervous system which is characterized by abnormal electrical activity of the brain. This disease affects the lives of millions of people. Although epilepsy can be treated in many cases with drug therapy, a significant number of patients are intractable to drug treatment. The aim of this research plan is to determine the cellular mechanisms of epilepsy in humans, in order to assist in developing improved treatments of seizure disorders. The cellular mechanisms of seizure activity will be investigated by studying the electrical events which occur during the transition between normal and abnormal neuronal behavior in epileptic human tissue. The dentate gyrus holds a crucial position in the control of electrical activity of the hippocampus, a site of seizure initiation. Therefore, the electrical activity of neurons in the dentate gyrus will be examined with intracellular techniques using brain slices from rat, monkey and epileptic patients. Comparison of data from experiments carried out on three species should resolve several important issues concerning studies of human tissue. The influence of excitatory and inhibitory synaptic input on hyperexcitability of the dentate gyrus will be examined. The role neurotransmitters play in modulating neuronal activity will be examined in detail with respect to low frequency synaptic input. The results from the proposed experiments will provide greatly needed information concerning the physiological basis of seizure disorders.