NMDA RECEPTOR-MEDIATED EXCITOPROTECTION OF CULTURED CEREBELLAR GRANULE NEURONS FAILS TO ALTER GLUTAMATE-INDUCED EXPRESSION OF C-FOS AND C-JUN MESSENGER-RNAS

Exposure of cultured cerebellar granule neurons to subtoxic concentrat ions of N-methyl-D-aspartate (NMDA) induces a state of excitoprotectio n when measured by subsequent exposure to toxic concentrations of glut amate. This NMDA-induced excitoprotective state is prevented by inhibi tors of new RNA and protein synthesis. Since the neurotrophic and exci toprotective effects of NMDA in cerebellar granule neurons may involve changes in the expression of the immediate early genes c-fos and c-ju n, we measured c-fos and c-jun mRNAs in cerebellar;granule neurons aft er exposure to either toxic concentrations of glutamate or excitoprote ctive (subtoxic) concentrations of NMDA. Exposure of cerebellar granul e neurons to toxic concentrations of glutamate induced a dramatic incr ease in c-fos and c-jun mRNAs which was not associated with a correspo nding increase in c-fos and c-jun proteins as measured immunocytochemi cally. However, the increase in c-fos and c-jun mRNAs induced by toxic concentrations of glutamate was not altered by preexposing cerebellar granule neurons to NMDA, suggesting that increased expression of c-fo s and c-jun mRNAs is not sufficient for glutamate toxicity of these ne urons. Preexposure of cerebellar granule neurons to NMDA for 24 h, whi ch induced a maximal excitoprotective state, resulted in a transient i ncrease in c-fos, and to a lesser degree c-jun, mRNAs similar to that induced by toxic concentrations of glutamate. The induction of c-fos, but not that of c-jun, mRNA both by excitoprotective concentrations of NMDA and by neurotoxic concentrations of glutamate was blocked by the non-competitive NMDA receptor antagonist, MK-801. These data show tha t c-fos and c-jun may play a role in NMDA receptor-mediated excitoprot ection as well as in NMDA receptor-mediated neurotoxicity. NMDA recept or-mediated excitoprotection is likely to interfere with the intracell ular cascade of glutamate toxicity by acting on an element downstream of c-fos and c-jun-dependent transcriptional regulation.