Mapping the cell-surface proteome underlying hippocampal mossy fiber synapse identity

Synaptic diversity is a key feature of neural circuits. Its underlying molecular basis is largely unknown, due to the challenge of analyzing the protein composition of specific synapse types. Here, we isolate the hippocampal mossy fiber (MF) synapse, taking advantage of its unique size and architecture, and dissect its proteome. We identify a rich cell-surface repertoire that includes adhesion proteins, guidance cue receptors, extracellular matrix (ECM) proteins, and proteins of unknown function. Among the latter, we find IgSF8, a previously uncharacterized neuronal receptor, and uncover its role in regulating MF synapse architecture and feedforward inhibition on CA3 pyramidal neurons. Our findings reveal a diverse MF synapse surface proteome and highlight the role of neuronal surface-ECM interactions in the specification of synapse identity and circuit formation.