DEPOLARIZATION OR GLUTAMATE-RECEPTOR ACTIVATION BLOCKS APOPTOTIC CELL-DEATH OF CULTURED CEREBELLAR GRANULE NEURONS

Cerebellar granule neurons can be readily maintained in culture if dep olarized with high concentrations of Ki or subtoxic concentrations of various excitatory amino acids. We now report that these depolarizing stimuli promote cerebellar granule neuron survival by blocking their p rogrammed death via apoptosis. Cerebellar granule neurons maintained i n depolarizing conditions and then changed to non-depolarizing conditi ons, exhibit the morphological and biochemical features of apoptosis, including cytoplasmic blebbing, condensation and aggregation of nuclea r chromatin and internucleosomal DNA fragmentation. Inhibitors of RNA or protein synthesis greatly attenuate cell death induced by non-depol arizing culture conditions. In contrast, cerebellar granule neurons, w hen exposed to fresh serum-containing medium or to high concentrations of glutamate, exhibit a delayed-type of neurotoxicity which is non-ap optotic in nature. Given the actions of excitatory amino acid receptor agonists in preventing apoptosis of cultured cerebellar granule neuro ns, we hypothesize that the functional innervation of postmigratory gr anule neurons during cerebellar development may prevent further elimin ation of these neurons by blocking their programmed death.