Abstract
Excitatory synapses are the most abundant synapse type in the brain. Being essential for behaviour and implicated in hundreds of brain disorders, these synapses exhibit striking structural and functional diversity. Synaptome mapping at single-synapse resolution reveals that synaptic protein diversity is spatially organised along the dendritic tree of individual neurons and varies with age and cell type. However, the cell biological mechanisms underlying the generation of these complex spatial synaptic patterns remain poorly understood. Potential mechanisms include somatic and dendritic protein synthesis, protein trafficking, and local regulatory mechanisms such as activity-dependent degradation. Here we developed computational models to test how combinations of these processes account for empirical synaptome data. We found that a combination of molecular transport mechanisms and local synaptic demand for proteins was sufficient to explain very 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.
Data availability
All research code is available on a GitHub repository (https://digitalresearchservices.ed.ac.uk/resources/eddie).
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Acknowledgements
The authors would like to thank D. Maizels for artwork, and M. Kiebler for comments on the manuscript. For the purpose of open access, the authors have applied a CC-BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Funding
OS, JDA and SGNG were supported by BBSRC Grant number BB/X009343/1, ‘Development of a computational model of synaptome architecture’. EB and SGNG were supported by European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (885069 SYNAPTOME).
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OS led the model development; EB led bioimage analysis; AS helped with scientific coding; SGNG and JDA worked on conceptual development and project management. All authors contributed to the writing and reviewed the manuscript.
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Sorokina, O., Bulovaite, E., Sorokin, A. et al. Protein trafficking and synaptic demand configure complex and dynamic synaptome architectures of individual neurons. Sci Rep (2026). https://doi.org/10.1038/s41598-026-40513-7
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DOI: https://doi.org/10.1038/s41598-026-40513-7
