title: Activity-induced synaptic delivery of the GluN2A-containing NMDA receptor is dependent on endoplasmic reticulum chaperone Bip and involved in fear memory.
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 Ca(2+)-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.
authors.affiliation: 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.
authors.forename: Xiao-min
authors.initials: XM
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Xun-yi
authors.initials: XY
authors.lastname: Yan
authors.affiliation: 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.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Mao
authors.initials: M
authors.lastname: Ye
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
authors.affiliation: 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.
authors.forename: Wen-bin
authors.initials: WB
authors.lastname: Qiang
authors.affiliation: 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.
authors.forename: Li-jun
authors.initials: LJ
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Yong-lan
authors.initials: YL
authors.lastname: Du
authors.affiliation: 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.
authors.forename: Xing-xing
authors.initials: XX
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Jia-sheng
authors.initials: JS
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.affiliation: Key Laboratory of Developmental Genes and Human Disease (Ministry of Education of China), Institute of Life Sciences, Southeast University, Nanjing, Jiangsu 211189, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Shuang
authors.initials: S
authors.lastname: Qiu
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Jian-hong
authors.initials: JH
authors.lastname: Luo
mesh_terms: D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005239:Fear / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D008568:Memory / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D006360:Heat-Shock Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP