Long term potentiation (LTP) in the hippocampus is a dramatic and well characterized example of activity-dependent synaptic plasticity in the central nervous system. Several recent studies have suggested that alterations in gene expression in response to neuronal activation contribute to this process. The finding that blockade of RNA and protein synthesis during or shortly after neuronal stimulation prevents the development of long-term changes in neuronal responsiveness has focused attention on genes that may be induced by neuronal stimulation. We and others have shown that mRNA levels for four transcription factor (TF) genes, zif/268, c-jun, jun-B and c-fos, as well as fos protein, are rapidly increased in rat brain following drug-induced seizures. In preliminary studies, we have recently found that except for c-fos, each of these genes are also induced in the dentate gyrus following LTP of the perforant path. These results have fueled speculation that the products of such genes may be important in synaptic plasticity. Here we propose to study the expression of four TF genes, zif/268, c-jun, jun-B, and c-fos following the induction of LTP in rat brain in vivo. Our central hypothesis is that LTP causes a cascade of gene activation controlled by the ordered expression of transcriptional regulatory proteins resulting in long term changes in synaptic efficiency. Initial studies will use in situ hybridization and Northern blot analysis to characterize the temporal and anatomic response of each of these genes to LTP produced by stimulating defined pathways: the perforant path from the entorhinal cortex to the dentate gyrus, and the Schaffer collaterals from CA3 to CA1. In the second phase, the pharmacology of these responses will be examined using NMDA antagonists, monamine depletion techniques, and protein kinase C (PKC) activators and inhibitors. In the third phase, techniques will be developed to perform in situ hybridization studies in the hippocampal slice preparation following physiological characterization and pharmacological manipulation in vitro. In this system both synapses described above will be examined, as will the CA3 region which supports both NMDA dependent and non-NMDA dependent forms of LTP. We anticipate that a detailed characterization of the response of early TF genes following LTP will provide important clues for understanding the downstream events involved in neuronal plasticity.
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