Synapses and Ca²⁺activity in oligodendrocyte precursor cells predict where myelin sheaths form

SUMMARYIn the nervous system, only one type of neuron-glial synapse is known to exist: that between neurons and oligodendrocyte precursor cells (OPCs). Neuron-OPC synapses are thought to bridge neuronal activity to OPCs. However, their composition, assembly, downstream signaling, andin vivofunctions remain largely unclear. Here, we use zebrafish to address these questions and identify postsynaptic molecules PSD-95 and Gephyrin in OPCs. They increase during early development and decrease upon OPC differentiation. PSD-95 and Gephyrin in OPCs are highly dynamic and frequently assemble at “hotspots.” Gephyrin “hotspots” and synapse-associated Ca2+activity in OPCs predict where myelin sheaths form in oligodendrocytes. Further analyses reveal that spontaneous synaptic release from neurons mediates most OPC Ca2+activity, while evoked synaptic release contributes only in early development. Finally, disruption of the synaptic molecule Nlgn3 impairs OPC differentiation and myelination. Together, we propose that neuron-OPC synapses are dynamically assembled and predetermine myelination patterns through Ca2+signaling.