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Numerous studies have indicated that nano-titanium dioxide (TiO 2 ) can induce neurotoxicity in vitro and in vivo , however, it is unclear whether nano-TiO 2 affects neurite outgrowth of hippocampal neurons. In order to investigate the mechanism of neurotoxicity, rat primary cultured hippocampal neurons on the fourth day of culture were exposed to 5, 15, and 30 μg/mL nano-TiO 2 for 24 h, and nano-TiO 2 internalization, dendritic growth, glutamate metabolism, expression of N-methyl- d -aspartate (NMDA) receptor subunits (NR1, NR2A and NR2B), calcium homeostasis, sodium current (I Na ) and potassium current (I K ) were examined. Our findings demonstrated that nano-TiO 2 crossed the membrane into the cytoplasm or nucleus, and significantly suppressed dendritic growth of primary cultured hippocampal neurons in a concentration-dependent manner. Furthermore, nano-TiO 2 induced a marked release of glutamate to the extracellular region, decreased glutamine synthetase activity and increased phosphate-activated glutaminase activity, elevated intracellular calcium ([Ca 2+ ]i), down-regulated protein expression of NR1, NR2A and NR2B, and increased the amplitudes of the I Na and I K . In addition, nano-TiO 2 increased nitric oxide and nitrice synthase, attenuated the activities of Ca 2+ -ATPase and Na + /K + -ATPase, and increased the ADP/ATP ratio in the primary neurons. Taken together, these findings indicate that nano-TiO 2 inhibits neurite outgrowth of hippocampal neurons by interfering with glutamate metabolism and impairing NMDA receptor function. [ABSTRACT FROM AUTHOR]