Oligodendrocytes use post-synaptic proteins to coordinate myelin formation on axons of distinct neurotransmitter classes

Axon myelination is a powerful method to tune neuronal circuit output through deposition of different patterns, lengths, and thicknesses of sheaths on many axon types. Yet the molecular mechanisms of myelin formation on distinct axon classes remain largely unknown. Recent work indicates that myelin properties on different neurons may be unique and function through distinct signaling pathways, and that neuronal activity and vesicle release promote myelin formation. Here, we use the zebrafish and the scaffold protein Gephyrin (Gphn) as a tool to examine post-synaptic protein function in OLs with respect to myelinated axon class identity. We show that Gphn protein is enriched in myelin sheaths that wrap GABAergic and glycinergic axons. Using Gphn loss-of-function approaches, we found an accumulation of long myelin sheaths across development that specifically wrap GABAergic axons. Loss of Gphn also biases glutamatergic axons for myelination at the expense of GABAergic axons. Collectively, our results suggest that OLs use post-synaptic machinery to coordinate myelin formation in an axon identity-dependent manner.