Consequences of recurrent seizures during early brain development

Abstract

It is well documented that prolonged seizures (status epilepticus) can cause neuronal injury and result in synaptic reorganization in certain brain regions. However, the effect of recurrent, relatively short seizures in young animals on subsequent brain development is not known. To study the consequences of recurrent seizures on the developing brain, we subjected immature rats to a total of 50 flurothyl-induced seizures from postnatal day 11 until day 23. Immunohistochemistry for c-fos was performed to characterize the pattern of neuronal activation following the seizures. Cell counting of dentate granule cells, CA3, CA1, and hilar neurons, using unbiased stereological methods, and the silver impregnation method were used to evaluate neuronal death following the recurrent seizures. Timm and Golgi staining were performed four weeks after the 50th seizure to evaluate the effects of recurrent seizures on synaptic organization. Our results show that recurrent flurothyl-induced seizures progressively increased excitability of the brain, as revealed by a dramatic increase in the extent and intensity of c-fos immunostaining. While no cell loss was detected in the hippocampus with either Cresyl Violet or silver stains, animals experiencing multiple daily seizures developed increased mossy fiber sprouting in both the supragranular layer of the dentate gyrus and the infrapyramidale layer of the CA3 region. Golgi staining confirmed that there was an increase in mossy fibers in the pyramidal cell layer. Our results suggest that serial recurrent seizures in the immature brain can lead to significant changes in mossy fiber distribution even though the seizures do not cause significant hippocampal cell loss.