Activity-induced synaptic delivery of the GluN2A-containing NMDA receptor is dependent on endoplasmic reticulum chaperone Bip and involved in fear memory

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.

成年前脑中的N -甲基- D -天冬氨酸受体（NMDAR）是一种异源四聚体，主要由两个GluN1亚基以及两个GluN2A和/或GluN2B亚基组成。含GluN2A和GluN2B的NMDAR在突触中的表达以及相对数量在控制钙离子依赖的信号传导和突触可塑性方面起着关键作用。先前的研究表明，NMDAR亚型的突触运输受到不同的调节，但精确的分子机制尚不清楚。在这项研究中，我们证明了内质网（ER）伴侣蛋白Bip选择性地与GluN2A相互作用，并介导了神经元活动诱导的含GluN2A的NMDAR从树突内质网的组装和突触整合。此外，干扰Bip和GluN2A之间相互作用的肽有效地破坏了GluN2A特异性的突触运输。有趣的是，在训练前对小鼠进行腹腔注射干扰肽会破坏其恐惧条件反射。总之，我们揭示了一种含GluN2A的突触NMDAR的活动依赖性供应的新机制，并证明了其与记忆形成的相关性。