The postsynaptic density in excitatory synapses is composed of clustered, heterogeneous nanoblocks.

The nanoscale organization of proteins within synapses is critical for maintaining and regulating synaptic transmission and plasticity. Here, we used cryo-electron tomography (cryo-ET) to directly visualize the three-dimensional architecture and supramolecular organization of postsynaptic components in both synaptosomes and synapses from cultured neurons. Cryo-ET revealed that postsynaptic density (PSD) is composed of membrane-associated nanoblocks of various sizes. Subtomogram averaging from synaptosomes showed two types (type A and B) of postsynaptic receptor-like particles at resolutions of 24 and 26 Å, respectively. Furthermore, our analysis suggested that potential presynaptic release sites are closer to nanoblocks with type A/B receptor-like particles than to nanoblocks without type A/B receptor-like particles. The results of this study provide a more comprehensive understanding of synaptic ultrastructure and suggest that PSD is composed of clustering of various nanoblocks. These nanoblocks are heterogeneous in size, assembly, and distribution, which likely contribute to the dynamic nature of PSD in modulating synaptic strength.