Developmental profile of core postsynaptic density protein complexes integrates signaling components of brain disorders

The postsynaptic density (PSD) contains a collection of scaffold proteins used for the assembly of synaptic signaling complexes and disruption of this signaling machinery might be implicated in a variety of brain disorders. However, it is not known how the core-scaffold machinery associates this collection of proteins through development and how proteins coding for genes involved in psychiatric and other brain disorders are distributed through spatio-temporal protein complexes. Here, using immunopurification, proteomics, bioinformatics and mouse genetics, we isolated 2876 proteins across 41 in-vivo protein complexes and determined their protein domain composition, correlation to gene expression levels, and developmental integration to the PSD. We defined major protein clusters for enrichment of schizophrenia (SCZ), autism spectrum disorders (ASD), developmental delay (DD), and intellectual disability (ID) risk factors at embryonic day 14 and the adult PSD. These protein complexes contained a discrete number of protein domains defining molecular functions. Mutations in highly-connected nodes alter protein-protein interactions that modulate the assembly of macromolecular complexes enriched in disease risk candidates. These results were integrated into a software platform: Synaptic Protein/Pathways Resource (SyPPRes), enabling the prioritization of brain disease risk factors and their placement within synaptic protein interaction networks.