Elsevier

Current Opinion in Neurobiology

Volume 47, December 2017, Pages 176-181
Current Opinion in Neurobiology

Schwann cells participate in synapse elimination at the developing neuromuscular junction

https://doi.org/10.1016/j.conb.2017.10.010Get rights and content

Highlights

  • Terminal Schwann cells actively participate in neuromuscular synapse elimination.

  • Neuregulin1 type-III is a key regulator of neonatal terminal Schwann cell behaviors.

  • Neonatal Schwann cell-like behaviors cause alteration of normally stable adult NMJs.

  • Neonatal Schwann cell behaviors are reactivated in various NMJ pathologies.

During the initial stages of innervation of developing skeletal muscles, the terminal branches of axons from multiple motor neurons form neuromuscular junctions (NMJs) on a small region of each muscle fiber, the motor endplate. Subsequently, the number of axonal inputs at the endplate region is reduced so that, at maturity, each muscle fiber is innervated by the terminals of a single motor neuron. The Schwann cells associated with the axon terminals are involved in the removal of these synapses but do not select the axon that is ultimately retained on each fiber. Schwann cells perform this function by disconnecting terminal branches from the myofiber surface and by attacking them phagocytically. Here we discuss how this behavior is regulated and argue that such regulation is not unique to development of neuromuscular innervation but is also expressed in the response of the mature NMJ to various manipulations and pathologies.

Introduction

The neuromuscular junction (NMJ) was the first synapse shown to undergo dramatic remodeling during early development. This remodeling is now termed ‘synapse elimination’. Because it was widely used as a model synapse to study synaptic transmission, it was known that each muscle fiber in most mammalian muscles is innervated by a branch of a single motor axon at a site near the center of each fiber (the ‘endplate’). Therefore, the discovery that each endplate is innervated by multiple axons during early postnatal development in rodent muscles came as a surprise [1]. This discovery was in fact a re-discovery of the multiple innervation described anatomically in early immature muscles by a student of Ramón y Cajal [2]. Very quickly it became clear that this multiple innervation was created by a constant pool of motor neurons innervating each muscle. Each motor neuron branched profusely and came to innervate an excessive number of endplates [3]. During early postnatal development, a competition among convergent axons for the sole occupancy of each motor endplate occurs. This competition ensured that only one, but in all cases at least one, of the initial inputs remained. The excess inputs were removed and the branching of each motor neuron reduced. As a result, the sizes of the motor units (the number of fibers innervated by each motor neuron) declined several-fold to the smaller adult level. Much of the initial work was accomplished through physiological analysis of muscle innervation and motor unit contractions. However, with the discovery of fluorescent proteins, their transgenic expression in motor neurons, and the production of fluorescent alpha-bungarotoxin (a snake toxin that functions as selective ligand for the nicotinic acetylcholine receptors (AChR) concentrated in the postsynaptic membrane at the endplate), elegant imaging of the elimination as it occurs at individual, identified endplates in living mouse muscles became possible [4••]. By this repeated imaging of the same NMJs in living animals (vital imaging), the fate of individual axons competing for the same postsynaptic receptors could be examined. This made it possible to determine that, at least in its final stages, the motor axons compete for the same synaptic space on each muscle fiber. The winning axon displaces the losing axon(s) and occupies the territory of the losers [4••]. The winner is not preordained as ablation of the axon of the apparent winning axon allows the apparent losing axon to win [5]. A number of experiments motivated by studies showing the importance of experience in development of the visual system were then conducted to demonstrate that the course of neuromuscular synapse elimination is heavily influenced by neural activity. Elimination could be slowed by inhibiting the transmission of impulses to NMJs and it could be sped up by increasing the impulse activity [6]. Some technically impressive experiments also demonstrated that the more active axon in the multiple innervation is favored in the competition at each endplate [7, 8•].

Section snippets

Terminal Schwann cells

Glia (Schwann cells) are present at NMJs and could play a role in this synapse elimination. Several non-myelinating ‘terminal Schwann cells’ (tSCs, also known as ‘perisynaptic Schwann cells’) are present at the NMJ. As shown by electron and light microscopy, their processes cap the branches of the adult nerve terminals that occupy the synaptic ‘gutters,’ the depressions in the muscle surface where AChR are highly concentrated. The tSCs come into close apposition with the muscle fiber only at

Terminal SCs respond to transmitter release and have a role in reinnervation upon nerve injury

Terminal SCs sense the presence of the innervating nerve terminal and probably the postsynaptic muscle fiber [12]. Upon denervation of the NMJ, the tSCs remain behind at the synapse but their behavior and their biochemistry change dramatically. The loss of the nerve is known to alter the expression of a host of genes, both positively and negatively. For instance, denervation leads to upregulation or downregulation of the intermediate filament proteins nestin and glial fibrillary acidic

Terminal SCs are active during developmental synapse elimination

Given the ability of tSCs to influence nerve growth and their location at the endplates of developing muscles, investigators have been interested in whether tSCs might play a role in synapse elimination [12•, 26•, 27••]. Smith et al. [27••] conducted a detailed light and electron microscopic study of this issue. They used fluorescence labeling of junctions in the sternomastoid muscle of mice near the time of birth to show that several tSCs are present at each endplate. At this stage the AChR

Control of terminal SC activities

These observations raise the issue of why tSCs should behave in this manner at developing NMJs but have a stable relationship with nerve terminals at adult junctions. Some of the neonatal behaviors of tSCs reappear during repair/reinnervation of mature synapses. Why do tSCs switch from a ‘maintenance’ mode to a phagocytic or ‘repair’ mode and vice versa [10, 12•]? There are clearly a number of cytokines and trophic factors that likely play a role. The expression of one of these factors, a motor

Conclusion

Schwann cells engage in activities that remodel synapses and nerve terminals under many circumstances throughout the life of the animal. These activities include intrusion into synapses and phagocytosis. Such activities must be carefully regulated to allow synaptic maintenance. Observations suggest that tSCs may promote synapse elimination by creating vacant synaptic sites that then can be reoccupied by the competing axon terminals. However, there is no evidence at present that these cells

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Supported by NIH grant NS20480 and by startup funds from Texas A&M University (to WT and MH). We thank UJ McMahan for comments on the manuscript.

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