Up-regulation of genes involved in cellular stress and apoptosis in a rat model of hippocampal degeneration

Changes in gene expression within the hippocampus induced by denervation af ter electrolytic fimbria-fornix lesion in rat were compared to morphologica l and biochemical alterations, Fimbria-fornix lesion results in degeneratio n of hippocampal cholinergic terminals as evidenced by a sustained (2 days tol month) decrease in cholineacetyltransferase (ChAT) activity (50%). Thes e changes were accompanied by a decrease in growth associated protein 43 (G AP-43) immunoreactivity in all hippocampal layers 4 days after lesion follo wed by a subsequent increase and return to normal levels by 20 days postinj ury. This increase in GAP-43 expression in the hippocampus between 7 to 20 days after lesion may reflect heterotypic sprouting, TUNEL-positive cells w ere revealed by in situ assay within the hippocampus at 10 days, but not at 3 days, after lesion. Two subtracted cDNA libraries from the dorsal hippoc ampus of control and injured rats (at 3 and 10 days postlesion) were constr ucted in order to search for new genes potentially implicated in degenerati on/regeneration phenomena. We analysed 1,536 clones from each library by di fferential screening and found a total of 46 up-regulated genes, Among the 15 known genes, 6 coded for proteins involved in signal transduction pathwa ys. The up-regulation of growth arrest DNA damage induced gene (GADD153), b rain-specific RING finger protein, JNK interacting protein (JIP-1), protein kinase A (PKA), and Na+K+ ATPase was studied by quantitative polymerase ch ain reaction (PCR). Two of these genes, GADD153 and JIP-1, have been previo usly shown to participate in cell modifications induced by stress and apopt osis, (C) 2000 Wiley-Liss, Inc.