Motor function recovery: deciphering a regenerative niche at the neuromuscular synapse

Abstract

The coordinated movement of many organisms relies on efficient nerve–muscle communication at the neuromuscular junction (NMJ), a peripheral synapse composed of a presynaptic motor axon terminal, a postsynaptic muscle specialization, and non‐myelinating terminal Schwann cells. NMJ dysfunctions are caused by traumatic spinal cord or peripheral nerve injuries as well as by severe motor pathologies. Compared to the central nervous system, the peripheral nervous system displays remarkable regenerating abilities; however, this capacity is limited by the denervation time frame and depends on the establishment of permissive regenerative niches. At the injury site, detailed information is available regarding the cells, molecules, and mechanisms involved in nerve regeneration and repair. However, a regenerative niche at the final functional step of peripheral motor innervation, i.e. at the mature neuromuscular synapse, has not been deciphered. In this review, we integrate classic and recent evidence describing the cells and molecules that could orchestrate a dynamic ecosystem to accomplish successful NMJ regeneration. We propose that such a regenerative niche must ensure at least two fundamental steps for successful NMJ regeneration: the proper arrival of incoming regenerating axons to denervated postsynaptic muscle domains, and the resilience of those postsynaptic domains, in morphological and functional terms. We here describe and combine the main cellular and molecular responses involved in each of these steps as potential targets to help successful NMJ regeneration.

Functional regeneration of the murine neuromuscular synapse relies on long-lasting morphological adaptations

“…Interestingly, studies using different paradigms of peripheral nerve damage have shown that morphological regeneration of the NMJ does not necessarily correlate with motor function recovery [ 22 ]. Likely, the functional rescue of neuromuscular synapses observed in murine species is limited by the denervation time frame and depends on the ability of the cellular components of the neuromuscular synapse to establish a permissive niche for NMJ regeneration [ 2 ]. In this context, our present findings show that NMJ reinnervation of the LAL muscle is accompanied by long-lasting changes in its three cellular components.…”

“…The NMJ is subjected to denervation due to traumatic injuries to peripheral nerves or pathologies. Even though the peripheral nervous system displays a comparatively higher regenerative capacity than the central nervous system, this capability is strongly dependent on the establishment of permissive cellular and molecular niches at the NMJ and the denervation-reinnervation time frame [ 2 ]. Therefore, a deep understanding of the cellular responses that allow proper synaptic function recovery is critical to design strategies to repair and/or to prevent the degeneration of the neuromuscular synapse during the denervation timespan.…”

Modulation of the Crosstalk between Schwann Cells and Macrophages for Nerve Regeneration: A Therapeutic Strategy Based on a Multifunctional Tetrahedral Framework Nucleic Acids System

“…The aim of nerve repair is the recovery of target muscle dyskinesia, which depends on the accuracy of motor endplate repair and the plasticity of the neuromuscular junction (NMJ) that is a tripartite, biochemical synapse that can transduce electrical impulses from the brain into voluntary contraction of muscle. [69,70] The plasticity of NMJ is determined by several elements, among which the improvement of repair activity by SCs is the most conducive to axon regeneration. [69] During PNI, SCs release various neurotrophic cytokines to support axon regeneration and nerve function recovery.…”

hiPSC-Derived Schwann Cells Influence Myogenic Differentiation in Neuromuscular Cocultures

“…One possible mode of action for the loss of AChR clusters could be a direct influence of SC on MN-derived agrin levels. At NMJs, matrix metalloproteinase-3 secreted by terminal SCs was found to cleave agrin and reduce its concentration in the synaptic basal lamina [ 98 , 99 , 100 ]. Conversely, AChR aggregates were increased in matrix metalloproteinase-3 null mice [ 101 , 102 ].…”