The proteomic landscape of synaptic diversity across brain regions and cell types

Neurons build synaptic contacts using different protein combinations that define the specificity, function, and plasticity potential of synapses; however, the diversity of synaptic proteomes remains largely plored. We prepared synaptosomes from 7 different transgenic mouse lines with fluorescently labeled synaptic terminals. Combining microdissection of 5 different brain regions with fluorescent-activated aptosome sorting (FASS), we isolated and analyzed the proteomes of 18 different synapse types. discovered similar to 1,800 unique synapse-type-enriched proteins and allocated thousands of proteins to different types of synapses (https://syndive.org/). We identify shared synaptic protein modules and highlight proteomic hotspots for synapse specialization. We reveal unique and common features of the dopaminergic proteome and discover the proteome signatures that relate to the functional properties different interneuron classes. This study provides a molecular systems-biology analysis of synapses a framework to integrate proteomic information for synapse subtypes of interest with cellular or circuit-level experiments.