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Neuromuscular synaptogenesis: coordinating partners with multiple functions

Nature Reviews Neuroscience volume 15, pages 703–718 (2014)Cite this article

Subjects

Key Points

  • Although it is fundamentally a simple synapse, the formation and maturation of the neuromuscular junction (NMJ) involves a complex molecular and activity-dependent crosstalk among presynaptic terminals, postsynaptic muscle fibres and glial cells. This crosstalk results in the tight assembly of an efficient and reliable communication unit.

  • The maturation of the NMJ involves precise and highly regulated molecular mechanisms. These mechanisms promote the clustering and stabilization of nicotinic acetylcholine receptors at the crest of postjunctional folds, as well as the differentiation of the presynaptic element to form active zones with proper synaptic proteins and clustered synaptic vesicles.

  • Presynaptic and postsynaptic maturation are interdependent and coordinated by common molecular and regulatory mechanisms. Glial cells also participate in synaptic maturation, which is dependent on both pre- and postsynaptic elements.

  • The NMJ undergoes activity-dependent maturation, which involves a drastic reduction in the number of presynaptic terminals via synaptic competition. The superseding nerve terminal is the one that delivers the most efficient synaptic communication (the strongest input) and that is in the best position to benefit from interactions with the muscle fibre and glial cells.

  • Glial cells at the NMJ regulate synaptic competition by clearing debris and participating in the elimination of supernumerary nerve terminals. They also actively decode the ongoing synaptic competition, discriminating competing inputs by detecting the levels of transmitter released from each competing nerve terminal. This enables these cells to then actively enhance the synaptic properties of a particular input to promote its survival.

Abstract

The formation of highly efficient and reliable synapses at the neuromuscular junction (NMJ) relies on dynamic molecular interactions. Studies of the development and maturation of the NMJ have focused on events that are dependent on synaptic activity and that require the coordinated actions of nerve- and muscle-derived molecules with different targets and effects. More recently, perisynaptic Schwann cells — the glial cells at NMJs — have become an important focus of research. These glia concomitantly contribute to pre- and postsynaptic maturation while undergoing maturation themselves. Thus, an intricate 'danse à trois' regulates the maturation of the NMJ to form a highly efficient communication unit, in which fine glial processes lie in close proximity to a highly concentrated population of postsynaptic receptors and perfectly aligned presynaptic release sites.

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Figure 1: Synapse formation at the NMJ: generating a functional communication unit.
Figure 2: Synaptic competition and elimination at the NMJ.
Figure 3: PSCs eliminate supernumerary connections.
Figure 4: PSCs can differentiate between competing synaptic terminals.

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Acknowledgements

The authors thank S. Carbonetto and A. Llobet for reading the manuscript and providing useful comments. This work was supported by grants from the Canadian Institutes for Health Research to R.R. (MOP-14137 and MOP-111070), a Leader Opportunity Fund from the Canadian Foundation of Innovation and an infrastructure grant from Fonds Recherche Québec-Santé (FRQ-S) to the GRSNC (Groupe de Recherche sur le Système Nerveux Central). At the time of writing, H.D. held a FRQ-S studentship.

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  1. Département de Neurosciences, Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, PO BOX 6128, Station Centre-Ville, Montréal, H3C 3J7, Québec, Canada

    Houssam Darabid, Anna P. Perez-Gonzalez & Richard Robitaille

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  1. Houssam Darabid
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Glossary

Neuromuscular junction

(NMJ). A unitary functional structure composed of a single axon terminal innervating a muscle fibre. The presynaptic terminal is covered by specialized glial cells called perisynaptic Schwann cells.

Perisynaptic Schwann cells

(PSCs). Non-myelinating glial cells at the neuromuscular junction. They originate from the neural crest but differ structurally and phenotypically from axonal myelinating or axonal non-myelinating Schwann cells.

Active zones

Areas on the surface of the presynaptic terminal that are characterized by their electron-dense appearance owing to the high concentration of proteins involved in Ca2+-dependent synaptic-vesicle exocytosis and recycling.

Motor columns

Groups of motor neurons that innervate selective sets of muscles.

Pre-patterning

A nerve-independent phenomenon that occurs prior to the arrival of motor axons whereby acetylcholine receptors cluster in the central region of the muscle fibres (along the longitudinal axis), purportedly defining the location of nerve–muscle contact.

AChR clustering

The gathering of acetylcholine receptors (AChRs), which is regulated by molecular mechanisms. It is one of the initial steps of synapse maturation.

Synapse elimination

A reduction in the number of synaptic contacts that results from activity-dependent synaptic competition.

Ganglioside

Member of a family of oligoglycosylceramide plasma-membrane lipids that was originally discovered after its isolation from ganglion cells and which is predominantly found in the nervous system. Antibodies against some disialosyl epitopes of gangliosides can be used to specifically ablate perisynaptic Schwann cells at the mammalian neuromuscular junction.

Retraction bulb

Enlarged distal part of the axon undergoing retraction (that is, axosomal shedding); it is commonly observed during synapse elimination.

Spike timing

Pattern of temporal correlation between presynaptic and postsynaptic activities. Synchronous and asynchronous patterns of activity are observed during early and late phases of synapse elimination, respectively.

Asynchronous activity

Uncorrelated timing of synaptic inputs onto the muscle fibre, leading to an out-of-phase activation.

PSC-receptor segregation

Spatial grouping and separation of receptors on the surface of perisynaptic Schwann cell (PSC) processes. Presumably, this grouping enables the PSC to detect neurotransmitter release from each competing terminal at dually innervated neuromuscular junctions. This segregation was described for purinergic type 2Y receptors, which mediate intra-PSC calcium activity during synaptic competition.

Muscle-twitch tension

Tension elicited by a muscle contraction that is evoked by a suprathreshold stimulation of the muscle or the nerve input.

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Darabid, H., Perez-Gonzalez, A. & Robitaille, R. Neuromuscular synaptogenesis: coordinating partners with multiple functions. Nat Rev Neurosci 15, 703–718 (2014). https://doi.org/10.1038/nrn3821

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