Loss of glial neurofascin155 delays developmental synapse elimination at the neuromuscular junction

Sarah L. Roche, Diane L. Sherman, Kosala Dissanayake, Geneviève Soucy, Anne Desmazieres, Douglas J. Lamont, Elior Peles, Jean-Pierre Julien, Thomas M. Wishart, Richard R. Ribchester, Peter J. Brophy, Thomas H. Gillingwater (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    27 Citations (Scopus)

    Abstract

    Postnatal synapse elimination plays a critical role in sculpting and refining neural connectivity throughout the central and peripheral nervous systems, including the removal of supernumerary axonal inputs from neuromuscular junctions (NMJs). Here, we reveal a novel and important role for myelinating glia in regulating synapse elimination at the mouse NMJ, where loss of a single glial cell protein, the glial isoform of neurofascin (Nfasc155), was sufficient to disrupt postnatal remodeling of synaptic circuitry. Neuromuscular synapses were formed normally in mice lacking Nfasc155, including the establishment of robust neuromuscular synaptic transmission. However, loss of Nfasc155 was sufficient to cause a robust delay in postnatal synapse elimination at the NMJ across all muscle groups examined. Nfasc155 regulated neuronal remodeling independently of its canonical role in forming paranodal axo-glial junctions, as synapse elimination occurred normally in mice lacking the axonal paranodal protein Caspr. Rather, high-resolution proteomic screens revealed that loss of Nfasc155 from glial cells was sufficient to disrupt neuronal cytoskeletal organization and trafficking pathways, resulting in reduced levels of neurofilament light (NF-L) protein in distal axons and motor nerve terminals. Mice lacking NF-L recapitulated the delayed synapse elimination phenotype observed in mice lacking Nfasc155, suggesting that glial cells regulate synapse elimination, at least in part, through modulation of the axonal cytoskeleton. Together, our study reveals a glial cell-dependent pathway regulating the sculpting of neuronal connectivity and synaptic circuitry in the peripheral nervous system.
    Original languageEnglish
    Pages (from-to)12904-12918
    Number of pages15
    JournalJournal of Neuroscience
    Volume34
    Issue number38
    DOIs
    Publication statusPublished - 17 Sep 2014

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