Mechanisms controlling neuromuscular junction stability

Abstract

The neuromuscular junction (NMJ) is the synaptic connection between motor neurons and muscle fibers. It is involved in crucial processes such as body movements and breathing. Its proper development requires the guidance of motor axons toward their specific targets, the development of multi-innervated myofibers, and a selective synapse stabilization. It first consists of the removal of excessive motor axons on myofibers, going from multi-innervation to a single innervation of each myofiber. Whereas guidance cues of motor axons toward their specific muscular targets are well characterized, only few molecular and cellular cues have been reported as clues for selecting and stabilizing specific neuromuscular junctions. We will first provide a brief summary on NMJ development. We will then review molecular cues that are involved in NMJ stabilization, in both pre- and post-synaptic compartments, considering motor neurons and Schwann cells on the one hand, and muscle on the other hand. We will provide links with pathologies and highlight advances that can be brought both by basic research on NMJ development and clinical data resulting from the analyses of neurodegeneration of synaptic connections to obtain a better understanding of this process. The goal of this review is to highlight the findings toward understanding the roles of poly- or single-innervations and the underlying mechanisms of NMJ stabilization.

Restoration of SMN in Schwann cells reverses myelination defects and improves neuromuscular function in spinal muscular atrophy

“…This suggests that improvements in some aspects of neuromuscular pathology in SMA can be generated by interventions that do not directly target motor neurons and/or skeletal muscle. Thus, improving the health of myelinating Schwann cells alone would be predicted to have a significant impact on NMJ stability of neighbouring motor neurons, and also improve neuromuscular function in SMA patients (41). The precise mechanisms through which Schwann cells can influence morphological and functional aspects of neuromuscular connectivity in health and disease are only beginning to be uncovered.…”

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

“…contacted by several different motor neurons (see Fig. 2A for an example) and, through a process called synapse elimination, go from being polyinnervated to monoinnervated by two weeks in mice 34,35 . In tandem, AChRs migrate and become concentrated in close apposition to motor nerve terminals, resulting in their conversion from simple, circular plaques at birth to complex pretzel-like structures with increasing numbers of perforations 36 .…”

What is Normal? Neuromuscular junction reinnervation after nerve injury

“…Functional motor recovery after peripheral nerve injury depends on two key factors: (1) nerve regeneration at the injury site; and (2) NMJ reinnervation within target muscle. The NMJ represents the interface of nerve and muscle and is composed of three main structures: the nerve terminal, which contains acetylcholine vesicles to be released across the synaptic cleft; the motor endplate covered in acetylcholine receptors (AChRs); and 3 to 5 nonmyelinating terminal Schwann cells (tSCs), or perisynaptic Schwann cells, that encase the nerve terminal and synapse . The NMJ is not a static structure as it undergoes continuous remodeling throughout the lifetime of the animal and after injury .…”