EPILEPTIC NEURONAL ACTIVITY AND HIPPOCAMPAL DAMAGE

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An experimental model has been developed to study the functional and structural consequences of seizure activity and to elucidate the normal structure and function of the hippocampus. Seizure activity in the hippocampus, which occurs in human temporal lobe epilepsy, the most common form of epilepsy, and in status epilepticus, a condition of continuous seizure discharge, is often associated with a characteristic pattern of hippocampal damage. This pattern of damage can be replicated in normal animals by electrical stimulation of the perforant path, the main afferent pathway to the hippocampus. Animals stimulated and allowed to recover for various periods can be used to determine the changes in function and structure that occur as a result of seizure activity. These animals therefore constitute a model of one aspect of the epileptic state, ie, the effects of repetitive seizures. Experiments have been designed to determine the relationship between selective neuron loss and the observed changes in both the excitability and inhibitory control of remaining neurons. Degeneration methods are used first to determine precisely which neurons are irreversibly damaged by seizure activity. The cells most sensitive will be identified as will the location of their efferent projections. Then, immunocytochemical methods are used to identify the neuroactive substances that may be depleted by the seizure-induced loss of susceptible neurons and interneurons. Since a long-lasting decrease in inhibition has been found to result from stimulation-induced seizures, the cells possibly responsible for this functional deficit will be identified. They will then be removed by means not involving seizures in order to determine which interneurons, when irreversibly damaged, might be responsible for the changes that occur after seizures. The long- term goals of this research are to describe the detrimental effects of seizure activity per se and to determine the mechanism by which seizures cause irreversible damage. This will allow the development of strategies to prevent epileptic brain damage and to retard the possibly progressive nature of the disorder.