Protein trafficking and synaptic demand configure complex and dynamic synaptome architectures of individual neurons

Excitatory synapses are the most abundant synapse type in the brain and are essential for behaviour and implicated in hundreds of brain disorders. These synapses exhibit striking structural and functional diversity, arising from differences in their proteomic composition and turnover. Synaptome mapping at single-synapse resolution reveals that this diversity is spatially organised along the dendritic tree of individual neurons. However, the cell biological mechanisms underlying the generation of these spatial synaptic patterns and their variation across neuron types and throughout the lifespan remain poorly understood. To investigate the contributions of somatic and dendritic protein synthesis, protein trafficking, and local regulatory mechanisms such as activity-dependent degradation, we developed computational models simulating these processes and compared their predictions with empirical synaptome data. We found that an extended sushi-belt model for spatial trafficking and local synaptic demand for proteins was sufficient to explain the complex profiles of synaptic protein distributions observed in young, mature and old mice and in different cell types. Our findings suggest the highly complex and dynamic synaptome architecture of the brain is an emergent property of a minimal set of cell biological processes. Our model sets the stage for simulations of brain tissue incorporating molecularly diverse neuronal and synaptic types in a synaptome and connectome architecture.