The long-term goal of the research project is to understand the mechanisms of seizure onset and termination using a rat model of limbic-circuit seizures. Electrophysiological, pharmacological and histochemical techniques will be utilized.
The specific aims of the present proposal are fourfold. The first hypothesis is that seizures are initiated in the brain by a combination of loss of inhibition and augmentation of excitation resulting in increased propagation of impulses through a neuronal circuit. Electrophysiological techniques will examine changes in excitation and inhibition in vivo where the circuits are intact. The second hypothesis is that the brain terminates seizure activity by the release of endogenous substances, such as nitric oxide, that act locally as antiepileptic agents. Nitric oxide synthase inhibitors will be tested for an effect on seizure onset and duration. The location and number of neurons that are NADPH-diaphorase positive will be determined after repeated seizures using histochemical techniques. The third hypothesis is that a single seizure alters the structure and function of the circuits involved in the seizure discharge, thus changing the probability of initiating a subsequent seizure in the same circuits. Changes in seizure threshold, changes in the interneuron population, sprouting of mossy fibers and cell death will be determined after a single seizure. The last hypothesis is that intrinsic properties of the dentate gyrus are sufficient to allow the expression of seizures, but inputs to the dentate gyrus regulate the onset and termination of seizures.This will be tested electrophysiologically in vitro where extrinsic and intrinsic properties of the dentate gyrus can be distinguished.
