Understanding the molecular diversity of synapses

Synapses are composed of thousands of proteins, providing the potential for extensive molecular diversity to shape synapse type-specific functional specializations. In this Review, we explore the landscape of synaptic diversity and describe the mechanisms that expand the molecular complexity of synapses, from the genotype to the regulation of gene expression to the production of specific proteoforms and the formation of localized protein complexes. We emphasize the importance of examining every molecular layer and adopting a systems perspective to understand how these interconnected mechanisms shape the diverse functional and structural properties of synapses. We explore current frameworks for classifying synapses and methodologies for investigating different synapse types at varying scales, from synapse-type-specific proteomics to advanced imaging techniques with single-synapse resolution. We highlight the potential of synapse-type-specific approaches for integrating molecular data with cellular functions, circuit organization and organismal phenotypes to enable a more holistic exploration of neuronal phenomena across different scales. The set of proteins present at synapses determines their heterogeneous functions and properties. In this Review, van Oostrum and Schuman describe the molecular mechanisms that contribute to the diversity of the synaptic proteome and consider how this molecular complexity can be captured by approaches for synapse classification.