REGULATION OF NEURONAL EXCITABILITY IN CHRONIC EPILEPTOGENESIS

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Clinical observations suggest that cortical malformations are an important etiological factor in the development of epilepsy, yet little is known about the mechanisms by which malformed cortex becomes prone to epileptogenesis. The planned experiments employ a model of a focal microgyrus in rat neocortex produced by a transcranial freeze lesion on the day of birth. The underlying pathology, when examined in mature animals, closely represents that of human microgyri. Electrophysiological recordings show that the area immediately adjacent to the microgyrus generates epileptiform activates. The planned experiments will test potential mechanisms by which this hyperexcitability might occur, namely a decrease in GABAa receptor-mediated inhibition and enhanced excitatory synaptic interactions due to altered intracortical circuitry. Techniques will involve use of neocortical slices maintained in vitro, and application of patch-clamp methods for recording spontaneous and evoked whole cell currents from neurons visualized in 'thin' slices, and those in standard slice preparations. Neuroanatomic studies will be done on neurons filled with biocytin, and in experiments where orthograde and retrograde tracers will be used to examine connectivity in and around the microgyrus. The results promise to provide new information about mechanisms for development of epileptogenesis in a prototypic cortical malformation.