EXCITATORY AMINO ACID-INDUCED CYTOTOXICITY IN PRIMARY CULTURES OF MOUSE CEREBELLAR GRANULE CELLS CORRELATES WITH ELEVATED, SUSTAINED C-FOS PROTOONCOGENE EXPRESSION

An elevated, sustained expression of c-fos mRNA was found in primary c ultures of mouse cerebellar granule cells following exposure to toxic concentrations of the excitatory amino acids, L-glutamate, L-homocyste ate, S-sulpho-L-cysteine and N-methyl-D-aspartate (NMDA), using leakag e of lactate dehydrogenase (LDH) as an indicator of cytotoxicity. In c ontrast, when used at non-toxic concentrations these compounds induced a rapid and transient increase in c-fos mRNA levels. Both LDH release and elevated, sustained c-fos mRNA induction were blocked (in the cas e of L-homocysteate) or reduced (in the case of L-glutamate and S-sulp ho-L-cysteine) by the selective NMDA receptor antagonist (DL(+/-)-2-am ino- 5-phosphonopentanoic acid) whereas 6-cyano-7-nitroquinoxaline-2,3 -dione (a selective antagonist at non-NMDA ionotropic receptors) had n o effect. These data suggest a role for altered c-fos mRNA expression in excitotoxic mechanisms.