BDNF gene expression is largely regulated by neuronal activity thereby implicating this regulatory process in the coordination of adaptive trophic responses to insult and in mechanisms of normal neuroplasticity. The applicant has demonstrated that activity dependent changes in BDNF mRNA content are suppressed by the adrenal hormones. Moreover, results indicate that BDNF transcripts I and II were co-regulated by activity and the adrenal hormones whereas BDNF transcripts III and IV were regulated by activity as immediate early genes. These findings suggest the hypothesis that, through the regulation of the different BDNF transcript forms, adrenal hormones have region specific effects on activity dependent BDNF expression and BDNF signaling. The goals of the proposed research are to test this hypothesis and predictions arising from it. Experiments are designed to evaluate the BDNF regulation at the level of mRNA expression, at the level of protein expression and trafficking, and at the level of trophic signaling. There are four specific aims. First, exon-specific in situ hybridization will be used to determine if adrenal hormones have cell- and transcript-specific effects on activity-induced increases in BDNF mRNA expression. Second, light and electron microscopic immunocytochemical techniques will be used to test the hypothesis that the newly expressed BDNF protein is preferentially anterogradely transported onto axonal and terminal arbors and depleted from those arbors by neuronal activity. Results from this study should indicate where increases in BDNF activity are expected to occur relative to regions of increased synthesis. Third, BDNF immunoassays will be used to test the hypothesis that adrenal hormones have region specific effects of seizure-induced increases in BDNF protein content. Finally, measures of tyrosine phosphorylation of the BDNF receptor trkB and NPY expression, thought to be regulated by BDNF following seizures, will be used to test the hypothesis that the adrenal hormones attenuate BDNF trophic signalling in a regional specific fashion.
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