Excitotoxicity mediated by overactivation of N-methyl-D-aspartate receptors (NMDARs) has been implicated in a variety of neuropathological conditions in the central nervous system (CNS).It has been suggested that NMDA neurotoxicity is developmentally regulated, but the definite pattern of the regulation has been controversial and the underlying mechanism remains largely unknown.Here, we show that NMDA treatment leads to significant cell death in mature (9,12DIV) hippocampal neurons or hippocampi of young (P12) and adult rats but not in immature (3,6DIV) neurons or embryonic (E18) and neonatal rat hippocampi.In contrast, NMDA promotes survival of immature neuron against tropic deprivation.Interestingly, it is found that NMDA preferentially activates p38 mitogen activated protein kianse (MAPK) in mature neuron and adult rat hippocampus, but favors extracellular signal-regulated kinasesl/2 (ERK1/2) activation in immature neuron and P0 rat hippocampus.Moreover, it is shown that NMDA neurotoxicity in mature neuron is mediated via p38 MAPK activation, and neuroprotection in immature neuron is mediated via ERK1/2 activation, while all these effects are NR2B-containing NMDARs dependent, as well as Ca2+ dependent.We also revealed that mature and immature neuron showed no difference in the amplitude of NMDA-induced intracellular calcium ([Ca2+]i) increase.However, the basal level of [Ca2+]i is shown to elevate with the maturation of neuron, and this elevation is attributable to the changes in NMDA neurotoxicity but not to the switch of NMDAR signaling pathway.Taken together, our results suggest that a switch of NMDA receptor-favorite intracellular signal pathways from ERK1/2 to p38 MAPK and the elevated basal level of [Ca2+]i with age might be critical for the developmental changes in NMDA neurotoxicity in hippocampal neuron.