Despite many advances in our knowledge regarding the cellular and molecular mechanisms underlying epilepsy, less progress has been made in those mechanisms involved in the spread of seizure activity and surround inhibition. With a more detailed knowledge of seizure propagation and surround inhibition, pharmaceutical and surgical treatments for epilepsy could be better devised. By using optical imaging and microelectrode recordings of rat, primate, and human models of epilepsy, the P.I. has the unique opportunity to gain a better understanding of those mechanisms involved in human neocortical epilepsy. This CIDA proposal focuses on neocortical mechanisms involved in seizure propagation and surround inhibition that are common between different models of epilepsy. Three epileptogenic stimuli will be applied to in vitro rat and human neocortical slices- including low-dose or focal application of bicuculline (GABA-A antagonist); increases in the extracellular potassium concentration; or photostimulation with caged glutamate. The interaction between neocortical regions in normal conditions will be studied and the neocortical layers that are prone to the initiation of seizure activity will be characterized. Then, the preferred and regional-specific pathways used for seizure propagation will be studied with microelectrode recordings (intra-/extra-cellular) and optical imaging. The nature of """"""""inhibitory"""""""" optical signals in areas surrounding the epileptic focus will be determined by correlating intracellular microelectrode recordings with optical imaging. Optical imaging and microelectrode recordings will also be used to examine pathways of seizure propagation and surround inhibition in the primate visual cortex and the intact human neocortex. In the primate, functional maps of visual cortex will be obtained and seizure activity will be evoked with focal applications or low-dose superfusion of bicuculline; superfusion of solutions with a high potassium concentrations; or microstimulation. In humans, as part of the routine determination of seizure thresholds for language mapping, microstimulation will be used to evoke focal epileptiform activity. In these intact preparations, the propagation of seizure activity over a larger surface area of cortex and the extent of surround inhibition will be monitored by optical imaging.
