Post-Synaptic Density Proteins in Oligodendrocytes are Required for Activity-Dependent Myelin Sheath Growth

SUMMARYCompelling evidence demonstrates a functional link between neuronal activity and myelination, highlighting the vital importance of axon-oligodendrocyte crosstalk in myelin physiology and function. However, how neuronal activity is relayed to oligodendroglia to regulate myelin formation remains not fully understood. Here, we aimed to characterize how that myelination is regulated by glutamate vesicular release in zebrafish spinal cord. We compared oligodendrocyte precursor cells (OPCs) and myelinating oligodendrocytes (mOLs) for their close apposition with pre-synaptic boutons and found that these are increased in number on mOLs during myelin internode elongation. Consistently, mOLs show more pre-synaptic boutons during myelin internode elongation compared to OPCs. 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 domains along their processes and sheaths, which are contacted by axonal pre-synaptic varicosities. These contacts are increased in mOLs. Importantly, CRISPR-Cas9 mediated deletion ofdlg4in oligodendroglia impairs myelin sheath growth, in vivo. Overall, our data indicate that PSD-95 is a key component of axons to oligodendrocytes neurotransmission that regulates myelin sheath growth.HIGHLIGHTSGlutamate vesicular release is required for myelinationAxon-oligodendroglia connectivity increases with oligodendrocyte maturationOligodendrocytes express the post-synaptic density protein 95Dlg4loss-of-function in oligodendroglia impedes myelin sheath growthGRAPHICAL ABSTRACT