INDUCTION OF C-FOS MESSENGER-RNA IN CEREBRAL-CORTEX BY EXCITOTOXIN STIMULATION OF CORTICAL INPUTS - INVOLVEMENT OF N-METHYL-D-ASPARTATE RECEPTORS

In this study we have characterized the induction of c-fos mRNA in cerebral cortex in response to unilateral kainate injection into the nucleus basalis. This treatment is associated with an intense stimulation of the ascending pathway and the subsequent induction of ornithine decarboxylase (ODC) enzyme activity and ODC mRNA in ipsilateral cerebral cortex which is sensitive to treatment with MK-801 and dihydropyridine antagonists. Unilateral injection of kainate into nucleus basalis caused a marked induction of c-fos mRNA in ipsilateral cortex which was detectable at 1 h, reached a maximal value at 8 h where c-fos mRNA levels were 16 times those in unoperated animals and then returned to control values by 24 h. However, the early induction of c-fos mRNA at 1 h was not related to a specific effect of kainate since, at this time point, sham-operated animals also showed a significant increase in the level of c-fos mRNA in ipsilateral cerebral cortex. No significant induction of c-fos mRNA was detected in ipsilateral cortex in sham-operated animals at 4 and 8 h after injection of vehicle. Treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (3 mg/kg) significantly attenuated the response obtained at 4 h and 8 h after kainate injection by 73% and 55% respectively, but did not influence the level of c-fos mRNA induced at 1 h. Delaying administration of MK-801 by 30 min reduced the effectiveness of this treatment on the response obtained at 4 h. The dihydropyridine antagonist, nimodipine had no effect on the induction of c-fos mRNA in response to kainate injection at 1, 4 or 8 h, indicating that ODC and c-fos mRNA are not induced by a common mechanism. These results demonstrate the induction of c-fos mRNA by two distinct mechanisms, one which is a rapid and transient response to tissue damage, and a second delayed and more substantial response which is initiated by excitotoxin stimulation and is mediated by NMDA receptors. Thus, NMDA receptors can regulate the expression of c-fos in cerebral cortex and hence may mediate effects produced in response to persistent neuronal excitation.