AGONIST-INDUCED DOWN-REGULATION OF NMDA RECEPTORS IN CEREBELLAR GRANULE CELLS IN CULTURE

In contrast to the acute toxic effect of NMDA on mature cerebellar gra nule cells, chronic treatment with NMDA (140 mu M from 1 to 9 days in vitro) did not compromise cell survival. Such treatment markedly suppr essed NMDA receptor activity: at 8 days in vitro NMDA-induced Ca-45(2) influx was reduced by similar to 60% and acute exposure to NMDA (hig hest concentration tested, 1 mM) at 9 days in vitro did not cause dete ctable toxicity. The reduction in NMDA receptor activity was accompani ed by a significant decrease (similar to 80% at 9 days in vitro) in th e level of the NR1 and the NR2A NMDA receptor subunit protein, detecte d using the selective photoaffinity ligand [I-125]CGP55802A. It seems, therefore, that the agonist-induced decrease in NMDA receptor activit y is due to receptor down-regulation. In contrast to the marked influe nce of chronic NMDA exposure on the cellular content of the NMDA recep tor subunit proteins, mRNA levels of the different subunits (NR1, NR2A , NR2B and NR2C) were not significantly affected. It seems, therefore, that agonist-induced down-regulation of the NMDA receptor involves cr itically mRNA translation and/or post-translational regulation.