We propose to investigate the mechanisms by which the activity of large numbers of neurons become synchronized to produce the widespread bursting activity characteristic of epilepsy. Much is known about how individual neurons produce bursts of activity. We must now study the mechanisms by which the bursting activity of individual neurons becomes synchronized into epileptiform activity. Neurophysiological experiments will be carried out in the CA2-CA3 region of the in vitro hippocampal slice preparation. Several different agents will be used to produce epileptiform activity: penicillin, chloride-deficient medium, picrotoxin, high potassium concentrations, kainic acid, enkephalin and barium. Two major questions will be addressed by the following experiments: 1) What changes in intercellular communication produces epileptiform synchronization? We will examine the changes in chemical synaptic (and possibly electrotonic) interactions between neurons which produce epileptiform bursting. These changes will be examined using simultaneous intracellular recordings of pairs of neurons under normal and epileptogenic conditions. We will measure the amount of synchronization as a function of epileptiform activity using cross-correlation analysis of the burst activity of pairs of neurons. 2) Does the intitiation of synchronous activity occur at discrete foci or does it result from a more diffuse build up of synchrony? This will be determined by multielectrode field potential spatial analysis of epileptiform activity. The different epileptogenic agents will be compared to determine if similar or different mechanisms can produce synchronization of the epileptiform activity of individual neurons. The long-term goal of these studies is an understanding of the mechanisms which produce epileptiform synchronous activity so that rational treatments for epilepsy can be developed. It seems particularly likely that means for desynchronizing epileptiform activity could be effective in treating epilepsy.
