GLUTAMATE-MEDIATED EXCITOTOXIC DEATH OF CULTURED STRIATAL NEURONS IS MEDIATED BY NON-NMDA RECEPTORS

Considerable interest has focused on the role of glutamate-mediated ex citotoxicity in neurodegenerative disorders of the basal ganglia. The in vitro data on the receptor mechanisms involved in this process, how ever, have been inconclusive. Some studies have indicated that excitot oxins acting at NMDA receptors kill striatal neurons and others have i ndicated that NMDA receptor-mediated excitotoxic death of striatal neu rons is minimal in the absence of cortex. In the present study, we use d a pharmacological approach to carefully reexamine this issue in a-we ek-old cultures of striatal neurons dissociated from E17 rat embryos. The sensitivity of these neurons to glutamate agonists and antagonists was determined by monitoring cell loss in identified regions of the g rowth dishes. We found that glutamate killed striatal neurons with an EC(50) of 100 mu M. This loss was not mediated by NMDA receptors, sinc e it was not reduced by the NMDA receptor antagonist APV (0.1-1.0 mM). Consistent with this result, up to 50 mM NMDA receptor-specific excit otoxin quinolinic acid (QA) did not affect neuronal survival. Depolari zing the QA-exposed neurons with 35 mM potassium chloride to enhance N MDA receptor activation by QA also did not produce neuron loss. The me tabotropic glutamate receptor antagonist AP3 (500 mu M) also had no ef fect on the striatal neuron loss produced by 100 mu M glutamate. In co ntrast, the non-NMDA antagonist GYKI 52466 (100 mu M) did block the ex citotoxic effect of glutamate (100 mu M). Specific AMPA and KA recepto r agonists and the non-NMDA antagonist GYKI 52466 revealed that the no n-NMDA receptor-mediated excitotoxic effect of glutamate was mediated by KA receptors. These results suggest that cultured striatal neurons are directly vulnerable to non-NMDA glutamate agonists, but not to NMD A and metabotropic glutamate agonists. Thus, non-NMDA receptors may pl ay a greater role in the excitotoxic death of striatal neurons in dise ase and experimental animal models than previously realized. (C) 1995 Academic Press, Inc.