Our understanding of epileptogenesis in the immature system is still quite limited, especially since the mechanisms that determine excitability of immature brain are likely to be different from those studied in mature CNS. The current proposal will examine cellular processes resulting from epileptogenic insults in the immature brain. Electrical stimulation, hyperthermia, and hypoxia will be used to trigger abnormalities in the hippocampal region of rat pups. Electrophysiological, morphological, and imaging techniques will be used to characterize the patterns of cellular abnormality arising from these insults. Field potential, intracellular, and whole-cell patch recordings will be obtained from identified neurons in thick and thin slices, and slice cultures of hippocampus. Extended hippocampal slices, including entorhinal cortex, will also be analyzed in an attempt to determine pathways of spread of excitability. Supplementing the traditional electrophysiological and morphological/immunocytochemical approaches will be two imaging techniques. Determinations of intracellular calcium levels will be carried out in an attempt to correlate cell damage with calcium fluxes resulting from traumatic injury. Voltage-sensitive dyes will be used to supplement electrophysiological analysis of excitability spread, especially in extended slices. Similar analyses will be carried out at short time intervals after the epileptogenic treatment, and at 3 and 6 months following treatment in order to determine whether there are long-term effects of these insults. With these approaches, we hope to be able to: a] determine the constellation of cellular parameters that are altered by epileptogenic treatments, as a function of treatment, age of the animal, and time after treatment; b] characterize the pattern of spread of excitability in immature brain; c] examine the correlation between intracellular rises in calcium and long-term functional and structural abnormalities; and d] correlate morphological/immunocytochemical damage with electrophysiological abnormalities. This information should provide insight into the special features of immature brain that influence its peculiar seizure susceptibility, and yield information about long-term changes resulting from immature seizure episodes that may render the adult brain more seizure-prone.
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