Post-synaptic density proteins in oligodendrocytes are required for activity-dependent myelin sheath growth

Neuronal activity regulates myelination in the central nervous system, highlighting the critical importance of axon-oligodendrocyte communications in myelin physiology and function. Here, we aimed to characterize how myelination is regulated by glutamate vesicular release in the zebrafish spinal cord. We compared oligodendrocyte precursor cells (OPCs) and myelinating oligodendrocytes (mOLs) for their close apposition with synaptophysin:GFP puncta and found that these are increased in number on mOLs during myelin internode elongation. In addition, we also found that oligodendroglial cells express the post-synaptic density protein 95 (PSD-95) along punctated domains, regardless of their differentiation stage. Genetically targeted PSD-95-GFP expression in oligodendroglia revealed post-synaptic-like microdomains along their processes and sheaths, which are contacted by axonal pre-synaptic varicosities. Importantly, the CRISPR-Cas9 mediated deletion of <i>dlg4a</i> in oligodendroglia impairs myelin sheath growth <i>in vivo</i>. Overall, our data indicate that PSD-95 is a key component of axons to oligodendrocytes neurotransmission that regulates myelin sheath growth.