Schwann cell guidance of nerve growth between synaptic sites explains changes in the pattern of muscle innervation and remodeling of synaptic sites following peripheral nerve injuries

Abstract

Terminal Schwann cells (SCs) are nonmyelinating glia that are a prominent component of the neuromuscular junction (NMJ) where motor neurons form synapses onto muscle fibers. These cells play important roles not only in development and maintenance of the neuromuscular synapse but also restoring synaptic function after nerve damage. In response to muscle denervation, terminal SCs undergo dramatic changes in their gene expression patterns as well as in their morphology, such as extending elaborate processes into inter‐junctional space. These SC processes serve as a path to guide axon terminal sprouts from nearby innervated junctions, promoting rapid reinnervation of denervated fibers. We studied the role of terminal SCs in synapse reformation by using two different fluorescent proteins to simultaneously label motor axons and SCs; we examined these junctions repeatedly in living animals using a fluorescence microscope. Here, we show that alterations in the patterns of muscle innervation following recovery from nerve injury can be explained by SC guidance of regenerating axons. In turn, this guidance leads to remodeling of the NMJ itself.

Examination of the human motor endplate after brachial plexus injury with two‐photon microscopy

“…There are animal data about the NMJ response to injury focused on terminal Schwann cells as well as molecular changes to the MEP, including the dispersion of acetycholine receptors . Long‐term denervation is accompanied by devolution of the MEP morphology from a mature “pretzel‐like” appearance (perforated with membranous infoldings) toward an immature plaque (diminished size/increased density) .…”

Wesley J. Thompson (1947–2019)

“…This work led to the demonstration that SC sprouts actually preceded and led the outgrowth of motor axons during reinnervation. Wes further showed that the coverage of denervated synaptic sites by remaining terminal SCs significantly influences which sites are reinnervated (Kang et al, 2003(Kang et al, , 2019. The creation of mouse lines with fluorescent SCs also led to other unanticipated, but nonetheless exciting and impactful observations.…”

Peripheral Nerve Regeneration and Muscle Reinnervation

“…Non-myelinating perisynaptic SCs (PSCs) are present at the endplate region of the neuromuscular junction where the motor nerve innervates the muscle fibers [116]. The cells respond to the acetylcholine released from the nerve terminals [117] and extend processes only when neuromuscular transmission is interrupted by partial or complete muscle denervation ( Figure 6K-P) [4,[116][117][118][119][120][121][122][123]. After partial nerve injury, the processes bridge between innervated and denervated junctions and thereby, they guide the axon sprouts emerging either from the last node of Ranvier of the intact nerve or from the terminal itself, to reinnervate the denervated endplates of neighboring muscle fibers ( Figure 6N-R) [5,121,122,124].…”