IMMEDIATE-EARLY GENE ACTIVATION DURING THE INITIAL PHASES OF THE EXCITOTOXIC CASCADE

Direct brain injections of the N-methyl-D-aspartate receptor agonist quinolinic acid (QA) trigger an excitotoxic cascade characterized by rapid neuronal death and glial/immune cell activation. The present study compared the timing of immediate early gene (IEG; c-fos, c-jun, jun-B, and zif/268) induction with the response of neuronal transcripts during the first 24 hr of a QA lesion within the rodent striatum. Following QA exposure, IEG mRNA induction periods extended from 30 min to 24 hr. Several characteristics of this prolonged transcriptional response suggest that separate cell populations (neuronal vs. glial) originate individual IEG phases during the first day of the lesion. The first IEG phase was rapid and peaked at 60 min. This initial IEG phase, likely neuronal in origin, was dominated by robust increases in the expression of c-fos, jun-B, and zif/268 mRNAs in contrast to small increases in c-jun expression. A second, delayed IEG phase was initiated after the first hour and extended to 24 hr. This IEG phase was more intense and continued beyond the period of neuronal survival as detected by the loss of neurotransmitter-specific mRNAs (preprotachykinin, preproenkephalin, and glutamic acid decarboxylase). During this phase, c-jun mRNA levels coordinately increased with c-fos. Interestingly, the transcriptional peak of the delayed IEG phase occurred between 4 and 12 hr, the time which corresponded to the rapid decline of neuronal transcripts. The temporal association of a delayed phase of IEG induction, possibly originating in nonneuronal cells, with neuronal death during the acute phases of the excitotoxic cascade suggest a link between glial IEG activation and the spreading cascade of neuronal damage characteristic of excitatory amino acid receptor overstimulation. (C)1993 Wiley-Liss, Inc.