Dissecting the cell-surface protein interaction network of a specific hippocampal synapse

Cell-surface proteins (CSPs), including transmembrane, membrane-bound and secreted proteins, are key regulators of precise patterns of neural connectivity. How CSPs control the development and plasticity of specific synaptic connections is largely unknown. The hippocampal mossy fiber (MF) synapse is an important information processing pathway that undergoes marked changes in response to sensory experience. We recently established a workflow to isolate MF synaptosomes from hippocampal tissue, allowing us to for the first time elucidate a synapse type-specific proteome. This is a crucial step forward, as previous approaches have mostly relied on bulk analysis of synaptosomes isolated from whole brain regions, resulting in averaging of their protein content. Here, we aim to dissect the CSP interaction network that orchestrates the development and plasticity of MF synapses. We will characterize the role of novel MF synapse-enriched CSPs in the development of this synapse. Further, we will unravel the network of extracellular interactions between all MF synapse-specific CSPs and map their precise synaptic localization. Finally, we will determine how this network changes in response to sensory experience. The results will generate key insight into the cell-surface interactions that specify MF synapses and uncover how these interactions change in response to sensory experience.