Compartmentalized distributions of neuronal and glial cell-surface proteins pattern the synaptic network

Neuronal identity and connectivity are closely linked. Single-cell sequencing studies show that different neuronal cell types express distinct combinations of cell-surface proteins important for synaptic connectivity and function. Emerging evidence indicates that glia-derived cell-surface proteins play critical roles in shaping connectivity as well. These studies begin to suggest that the proteins present on presynaptic and postsynaptic membranes, glial processes, and secreted into the synaptic cleft and extracellular matrix together confer unique surface identities to different types of synaptic connections. Here, we summarize recent findings demonstrating that cell-surface proteins derived from both neurons and glia interact and cooperate to control the connectivity, architecture and function of specific synapses.status: publishe

Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer

Excitatory and inhibitory neurons are connected into microcircuits that generate circuit output. Central in the hippocampal CA3 microcircuit is the mossy fiber (MF) synapse, which provides powerful direct excitatory input and indirect feedforward inhibition to CA3 pyramidal neurons. Here, we dissect its cell-surface protein (CSP) composition to discover novel regulators of MF synaptic connectivity. Proteomic profiling of isolated MF synaptosomes uncovers a rich CSP composition, including many CSPs without synaptic function and several that are uncharacterized. Cell-surface interactome screening identifies IgSF8 as a neuronal receptor enriched in the MF pathway. Presynaptic Igsf8 deletion impairs MF synaptic architecture and robustly decreases the density of bouton filopodia that provide feedforward inhibition. Consequently, IgSF8 loss impairs excitation/inhibition balance and increases excitability of CA3 pyramidal neurons. Our results provide insight into the CSP landscape and interactome of a specific excitatory synapse and reveal IgSF8 as a critical regulator of CA3 microcircuit connectivity and function.status: publishe