Supramolecular organization of the postsynaptic density for trans-synaptic alignment in excitatory synapse observed by cryo-electron tomography.

Abstract

Nanoscale organization of proteins within synapses are critical for maintaining and regulating synaptic transmission and plasticity. Revealing the supramolecular structure of synapses will lead to better understanding of synaptic functions in the brain, which feeds through to new therapeutic strategies and clinical trials. In this study, we used cryo-electron tomography to directly visualize in situ three-dimensional architecture and supramolecular organization of trans-synaptic nanocolumns in their native cellular context. Our findings strongly suggested a standard trans-synaptic nanocolumn contains a synaptic vesicle at release site, a cluster of postsynaptic receptors and a PSD nanodomain, together creating a physical transcellular alignment. Quantitative analyses revealed PSD nanodomain is the basic unit and form different sizes of PSD clusters. Furthermore, high-resolution tomograms obtained from the synaptosome sample allows us to detect the glutamate receptor-like particles and putative adhesion molecules. These results clarify unresolved issues regarding the ultrastructural features of synapses and support the idea that trans-synaptic alignment exists to carry out synaptic functions. The supramolecular architecture of the basic PSD nanodomain and its clusters suggests a higher-order organization of trans-synaptic nanocolumn of central nervous system synapses to maintain and regulate synaptic transmission.