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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Acknowledgements
This work was supported by grants from the National Basic Research Program of China (2010CB912002), the National Natural Science Foundation of China (91232303, 81221003, 81371302 and 31460258) and the Fundamental Research Funds for the Central Universities of China. We thank Dr Guoqiang Bi from the University of Science and Technology of China for his help with STORM and other cell imaging experiments.
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Supplementary information, Figure S1
(A) BFA or CBM applying disrupts ER-to-Golgi transport in dendrites. (PDF 32 kb)
Supplementary information, Figure S2
(A) CHX was applied simultaneous or 0.5 h before depolarization (KCl) or cLTP stimulation. (PDF 37 kb)
Supplementary information, Figure S3
(A,B) The orginal gel of Figure 7C. (PDF 54 kb)
Supplementary information, Figure S4
(A) Quantification of the effect of disrupting peptides on surface expression of GluN2A-containing NMDARs induced by neuronal activity. (PDF 2898 kb)
Supplementary information, Movie S1
Transport of mitochondria along microtubules was inhibited by nocodazole Mitochondria were labeled by mitotracker in living neurons and tracked under a fluorescent confocal microscope under basal condition. (MOV 630 kb)
Supplementary information, Movie S2
Transport of mitochondria along microtubules was inhibited by nocodazole Mitochondria were labeled by mitotracker in living neurons and tracked under a fluorescent confocal microscope under nocodazole treatment conditions. (MOV 656 kb)
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Zhang, Xm., Yan, Xy., Zhang, B. et al. Activity-induced synaptic delivery of the GluN2A-containing NMDA receptor is dependent on endoplasmic reticulum chaperone Bip and involved in fear memory. Cell Res 25, 818–836 (2015). https://doi.org/10.1038/cr.2015.75
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DOI: https://doi.org/10.1038/cr.2015.75
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