CYTOKINES ARE INCREASED IN THE RAT HIPPOCAMPUS AFTER SEROTONERGIC NEURON DEGENERATION AND UP-REGULATE THE EXPRESSION OF GDH, AN ENZYME INVOLVED IN GLUTAMATE DETOXIFICATION

The degeneration of serotonergic neurons increases the expression of g lutamate dehydrogenase (GDH) in hippocampal astrocytes. This process w as demonstrated to be independent of the serotonin level. At the same time, upregulation of tumor necrosis factor (TNF) alpha and interleuki n (IL)-1 alpha mRNA were observed, whereas levels of transforming grow th factor (TGF) beta 1 mRNA remained unchanged. The level of GDH mRNA was increased in primary cultures of hippocampal astrocytes treated wi th TNF alpha and IL-1 alpha suggesting that these cytokines act on the GDH metabolism. TNF alpha and IL-1 alpha induced an increase in GDH p romoter activity in C8S (an astrocytic cell line) transfected with con structs containing 5' flanking genomic sequences of GDH driving the ex pression of a reporter gene. These observations suggest that cytokines may be signals that upregulate the astrocytic GDH expression in respo nse to the degeneration of serotonergic terminals in the hippocampus.