The brain-derived neurotrophic factor (BDNF) affects the developing cerebellar granule cells. Exposure of 9-11-day-old primary cultures of rat cerebellar granule neurones for 3 h to a more depolarizing medium (additional 15-30 mM KCl) stimulated the release of glutamate and increased the BDNF mRNAs levels. This BDNF and mRNA upregulation was inhibited by dizocilpine (MK-801), the noncompetitive blocker of N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors, and mimicked by NMDA. Continuous (up to 5 h) culture exposure to non-toxic NMDA concentration resulted in a prolonged increase in BDNF mRNA expression and enhanced neuronal resistance to glutamate toxicity. The latter effect of NMDA was attenuated by cycloheximide, a protein synthesis inhibitor. The mechanisms responsible for NMDA-triggered BDNF upregulation and neuroprotection might be important in the compensatory response of brain to excitotoxicity.