Recent studies using a variety of neuronal systems strongly suggest that the expression of putative neurotransmitter / neuromodulatory substances is affected by physiological activity. The PI's work has demonstrated that recurrent limbic seizures differentially influence the regulation of three neuropeptides contained within the hippocampal mossy fiber system: enkephalin synthesis and concentration is increased whereas immunoreactivity for dynorphin is reduced and immunoreactivity for CCK is eliminated. Recent in situ hybridization studies indicate that seizure-induced increases in enkephalin transcription are broadly distributed across limbic forebrain and are associated, in at least some areas, with increased transcription of the proto-oncogene c-fos. There are four major goals to the proposed research. First, the regional distribution of seizure-induced alterations in the abundance of mRNAs for preproenkephalin A, preprocholecystokinin, and glutamic acid decarboxylase will be mapped in forebrain with particular interest in determining whether seizures have a consistent influence over each mRNA species in different brain areas and whether there is evidence for differential regulation in areas of colocalization. Second, in situ hybridization techniques will be used to test if there is good regional correspondence between the seizure-induction of c-fos and preproenkephalin A mRNA as would be expected if increased c-fos transcription is important for the later alterations in enkephalin expression. Third, the influence of repetitive afferent stimulation on the abundance of mRNAs for preproenkephalin A and the preprocholecystokinin will be examined in hippocampus and piriform cortex. The results of this experiment will be of considerable utility in evaluating the hypothesis that the effects triggered by seizures are exaggerated versions of events that occur under more normal physiological circumstances. Fourth, the influence of recurrent limbic seizures on the incidence of dentate gyrus granule cell somatic spines and soma-somatic junctions will be evaluated. These studies should contribute to the understanding of how the expression of messenger molecules is regulated in brain, provide data on the cellular consequences of recurrent seizures, and generate new information regarding the possibility that intense physiological activity effects long- lasting changes in the operation of brain circuities via alterations in genomic expression.
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