Studies On The Molecular Mechanism Of NMDA Receptor-mediated Neuronal Excitotoxicity

N-methyl-D-aspartate(NMDA)receptor is a kind of Ionotropic glutamate receptors.As an important part of the postsynaptic membrane of excitatory synapses,it plays an essential role in synaptic transmission and synaptic plasticity.Overexpression of NMDA receptors leads to calcium-dependent excitotoxicity,which is also involved in neural damage resulting from cerebral ischemia.However,the mechanism underlying NMDA receptor-mediated excitotoxicity remains unclear.In this study,we confirmed that excessive activation of NMDARs led to cell apoptosis in PC12 cells,which was mediated predominantly by the GluN2B-containing,but not the GluN2A-containing NMDARs.In addition,Clathrin-dependent endocytosis participated in NMDA-induced excitotoxicity.Furthermore,we identified that GluN2B-containing NMDARs underwent endocytosis during excessive NMDA treatment.Peptides specifically disrupting the interaction between GluN2B and AP-2 complex not only blocked endocytosis of GluN2B induced by NMDA treatment,but also abolished NMDA-induced excitotoxicity.These results demonstrate that Clathrin-dependent endocytosis of GluN2B-containing NMDARs is critical to NMDA-induced excitotoxicity in PC 12 cells and in primary cultured cortical neurons,and therefore provide a novel target for blocking NMDAR-mediated excitotoxicity.