ABSTRACT Synapses are the most abundant and distinguishing feature of the brain, providing enormous functional diversity and plasticity to neural circuits. These structures are incredibly small, less than 1 femtoliter in volume, and remarkably plastic in their functional properties. Unique ensembles of protein networks that are enriched within postsynaptic structures orchestrate the development, maintenance, and plasticity of synapses. Genetic mutations associated with risk for intellectual disability, schizophrenia, autism, and other developmental brain disorders (DBDs) are predominated by genes encoding synaptic proteins. These observations have led to the hypothesis that many DBDs are synaptopathologies that alter synaptic development and function. However, while histological evidence in human postmortem samples and mouse models supports this theory, the molecular mechanisms of synaptic pathology remain poorly understood. This proposal will address this gap in knowledge by combining recent advances in CRISPR-genome editing paired with two highly innovative proteomics approaches we have developed to enable: 1) the discovery of synaptic protein complexes in vivo that are associated with DBDs and 2) how these complexes are disrupted in diverse models of DBD. This will significantly advance our understanding of potential synaptopathic mechanisms that may be comorbid across DBD mutations. Uncovering these molecular mechanisms of synaptopathology can be expected to lead to better insights of disorder etiology and potential therapeutic approaches.