Corticosteroid therapy is widely used during the third trimester of pregnancy to prevent respiratory distress syndrome in prematurely born neonates. A single course of this therapy has no long-term harmful effects. However, multiple courses of corticosteroid therapy with long-lasting elevations of corticosteroids are frequently used. Animal data indicate that long-term prenatal corticosteroid increases during the last third of pregnancy may adversely affect brain development, especially hippocampus-associated functions such as learning and memory. The purpose of this proposal is to establish a rat model of prenatal or early postnatal multiple-course corticosteroid administration to determine the effects of repeated corticosteroid therapy on hippocampal function (tested postnatally in hippocampal- related seizure susceptibility, behavioral and learning tests in vivo) and morphology (assessed using neuronal proliferation, stereological neuronal counts, and rate of neuronal death). The proposal will further investigate the possibility that there may be a synergy between the effects of such doses of corticosteroids that do not produce harmful effects and the effects of another subthreshold postnatal impact (a febrile seizure). The synergy of these two factors will then result in adverse effects on hippocampal function and structure (""""""""two-hit"""""""" hypothesis). Finally, the experiments will determine whether the harmful effects of repeated corticosteroid treatment may be ameliorated by the exposure of the affected offspring to an enriched environment. Methods include prenatal administration of corticosteroids, kainic acid-induced seizures, hippocampal kindling, open field, horizontal bar and elevated plus maze tests, labeling of newly born neurons with BrdU, fluorescent staining for apoptotic/necrotic neurons, stereological neuronal counts in the hippocampus using light and confocal microscopy, and the exposure of the rats to an enriched environment. The data of this proposal will be critical for determining long-term adverse effects of multiple course prenatal corticosteroid therapy and for the ameliorating these effects in the offspring.
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