Supramolecular organization of NMDA receptors and the postsynaptic density

•Complexes, supercomplexes and nanodomains are building blocks of the synapse.•A tripartite mechanism dictates NMDA receptor complex assembly into supercomplexes.•In vivo genetics rejects classical PDZ model of NMDA receptor-MAGUK assembly.•Genetic rules predict the developmental timing of synapse supramolecular assembly.

The postsynaptic density (PSD) of all vertebrate species share a highly complex proteome with ∼1000 conserved proteins that function as sophisticated molecular computational devices. Here, we review recent studies showing that this complexity can be understood in terms of the supramolecular organization of proteins, which self-assemble within a hierarchy of different length scales, including complexes, supercomplexes and nanodomains. We highlight how genetic and biochemical approaches in mice are being used to uncover the native molecular architecture of the synapse, revealing hitherto unknown molecular structures, including highly selective mechanisms for specifying the assembly of NMDAR-MAGUK supercomplexes. We propose there exists a logical framework that precisely dictates the subunit composition of synaptic complexes, supercomplexes, and nanodomains in vivo.