Activity-induced synaptic delivery of the GluN2A-containing NMDA receptor is dependent on endoplasmic reticulum chaperone Bip and involved in fear memory |
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Authors: | Xiao-min Zhang Xun-yi Yan Bin Zhang Qian Yang Mao Ye Wei Cao Wen-bin Qiang Li-jun Zhu Yong-lan Du Xing-xing Xu Jia-sheng Wang Fei Xu Wei Lu Shuang Qiu Wei Yang Jian-hong Luo |
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Institution: | 1.Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China;2.Department of Physiology, Kunming Medical University, Kunming, Yunnan 650500, China;3.Key Laboratory of Developmental Genes and Human Disease (Ministry of Education of China), Institute of Life Sciences, Southeast University, Nanjing, Jiangsu 211189, China |
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Abstract: | The N-methyl-D-aspartate receptor (NMDAR) in adult forebrain is a heterotetramer mainly composed of two GluN1 subunits and two GluN2A and/or GluN2B subunits. The synaptic expression and relative numbers of GluN2A- and GluN2B-containing NMDARs play critical roles in controlling Ca2+-dependent signaling and synaptic plasticity. Previous studies have suggested that the synaptic trafficking of NMDAR subtypes is differentially regulated, but the precise molecular mechanism is not yet clear. In this study, we demonstrated that Bip, an endoplasmic reticulum (ER) chaperone, selectively interacted with GluN2A and mediated the neuronal activity-induced assembly and synaptic incorporation of the GluN2A-containing NMDAR from dendritic ER. Furthermore, the GluN2A-specific synaptic trafficking was effectively disrupted by peptides interrupting the interaction between Bip and GluN2A. Interestingly, fear conditioning in mice was disrupted by intraperitoneal injection of the interfering peptide before training. In summary, we have uncovered a novel mechanism for the activity-dependent supply of synaptic GluN2A-containing NMDARs, and demonstrated its relevance to memory formation. |
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Keywords: | NMDA receptors endoplasmic reticulum Bip non-canonical trafficking fear conditioning |
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