Interdisciplinary Institute for Neuroscience, University of Bordeaux, UMR 5297, 33076 Bordeaux, France;
CNRS, IINS UMR 5297, Bordeaux, France.
Proc Natl Acad Sci U S A. 2020 Sep 29;117(39):24526-24533. doi: 10.1073/pnas.1922477117. Epub 2020 Sep 14.
Hippocampal pyramidal neurons are characterized by a unique arborization subdivided in segregated dendritic domains receiving distinct excitatory synaptic inputs with specific properties and plasticity rules that shape their respective contributions to synaptic integration and action potential firing. Although the basal regulation and plastic range of proximal and distal synapses are known to be different, the composition and nanoscale organization of key synaptic proteins at these inputs remains largely elusive. Here we used superresolution imaging and single nanoparticle tracking in rat hippocampal neurons to unveil the nanoscale topography of native GluN2A- and GluN2B-NMDA receptors (NMDARs)-which play key roles in the use-dependent adaptation of glutamatergic synapses-along the dendritic arbor. We report significant changes in the nanoscale organization of GluN2B-NMDARs between proximal and distal dendritic segments, whereas the topography of GluN2A-NMDARs remains similar along the dendritic tree. Remarkably, the nanoscale organization of GluN2B-NMDARs at proximal segments depends on their interaction with calcium/calmodulin-dependent protein kinase II (CaMKII), which is not the case at distal segments. Collectively, our data reveal that the nanoscale organization of NMDARs changes along dendritic segments in a subtype-specific manner and is shaped by the interplay with CaMKII at proximal dendritic segments, shedding light on our understanding of the functional diversity of hippocampal glutamatergic synapses.
海马锥体神经元的特征是具有独特的分支，分为分离的树突域，接收具有特定性质和可塑性规则的不同兴奋性突触输入，这些规则决定了它们各自对突触整合和动作电位发放的贡献。虽然已知近端和远端突触的基本调节和可塑性范围不同，但这些输入处关键突触蛋白的组成和纳米级组织在很大程度上仍然难以捉摸。在这里，我们使用大鼠海马神经元中的超分辨率成像和单颗粒追踪技术，揭示了在树突分支上，在谷氨酸能突触的依赖使用适应性中起关键作用的天然 GluN2A- 和 GluN2B-NMDA 受体（NMDAR）的纳米级拓扑结构。我们报告了在近端和远端树突段之间 GluN2B-NMDAR 的纳米级组织发生了显著变化，而 GluN2A-NMDAR 的拓扑结构在整个树突上保持相似。值得注意的是，近端段 GluN2B-NMDAR 的纳米级组织依赖于其与钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）的相互作用，而在远端段则不是这样。总的来说，我们的数据表明，NMDAR 的纳米级组织以亚型特异性的方式沿树突段发生变化，并受近端树突段 CaMKII 的相互作用影响，这为我们理解海马谷氨酸能突触的功能多样性提供了新的认识。
