Mechanism of synapse disassembly at the developing neuromuscular junction

doi:10.1016/S0959-4388(96)80015-8

Current Opinion in Neurobiology

Volume 6, Issue 1, February 1996, Pages 104-112

https://doi.org/10.1016/S0959-4388(96)80015-8 Get rights and content

Abstract

Throughout the developing nervous system of higher vertebrates, synaptic connections are concurrently being established and eliminated. The consequence of this synaptic remodeling is that axons strengthen their connections with some targets while completely disconnecting from other postsynaptic cells. The transition from multiple to single axonal innervation of skeletal muscle fibers is the most accessible example of this developmental reorganization. In muscle, the elimination of axonal input appears to be driven by a protracted competition between different axons co-innervating the same junction, with the muscle fiber as intermediary. Asynchronous synaptic activity may be the factor that differentiates the competing inputs. In some circumstances, synapses can also be lost in ways that are independent of activity. Similarities between activity-dependent and activity-independent synapse elimination provide insights into mechanisms underlying developmental synaptic reorganization.

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Cited by (101)

Developmental neuromuscular synapse elimination: Activity-dependence and potential downstream effector mechanisms
2020, Neuroscience Letters
Citation Excerpt :
Moreover, discussion is limited to observations made during early postnatal stages and does not include studies of synapse elimination that occur in adult muscles following injury-induced denervation and subsequent reinnervation of motor endplates by multiple motor axons. A more thorough review of the literature may be found elsewhere [45,51,85]. This article is meant to (1) summarize how the motor neurons, synaptic glia and muscle fibers are known to contribute to the developmental phenomenon and (2) speculate how the synapse modifying cellular activities may be regulated.
Synaptic connections initially formed during nervous system development undergo a significant transformation during nervous system maturation. Such maturation is essential for the proper architecture and function of the nervous system. Developmental synaptic transformation includes “synapse elimination,” a process in which multiple immature presynaptic inputs converge at and compete for control of a common postsynaptic target. This developmental synaptic remodeling is best understood at mammalian neuromuscular junctions. It is well established that neuromuscular activity provides the impetus for the pruning of redundant motor axon inputs. Despite the dominant influence neuromuscular activity exerts on developmental synapse elimination, however, the downstream mechanisms of neuromuscular activity that affect synapse elimination remain poorly understood. Conversely, although several cellular and molecular effector mechanisms are known to impact synapse elimination, it is unclear whether they are modulated by neuromuscular activity. This review discusses how the motor neurons, synaptic glia and muscle fibers each contributes to the developmental phenomenon, and speculates how neuromuscular activity may modulate these contributions.
MHCI promotes developmental synapse elimination and aging-related synapse loss at the vertebrate neuromuscular junction
2016, Brain, Behavior, and Immunity
Citation Excerpt :
The canonical model for studying developmental synapse elimination is the vertebrate neuromuscular junction (NMJ) (Brown et al., 1976; Thompson, 1985). Before birth, each muscle fiber receives inputs from many motor neurons (MNs) (Nguyen and Lichtman, 1996; Sanes and Lichtman, 1999; Tapia et al., 2012). MN axon branches are extensively pruned, and by the end of the second postnatal week in rodents, each muscle fiber receives input from only a single MN (Brown et al., 1976; Busetto et al., 2000; Keller-Peck et al., 2001; Personius and Balice-Gordon, 2001; Redfern, 1970).
Synapse elimination at the developing neuromuscular junction (NMJ) sculpts motor circuits, and synapse loss at the aging NMJ drives motor impairments that are a major cause of loss of independence in the elderly. Here we provide evidence that at the NMJ, both developmental synapse elimination and aging-related synapse loss are promoted by specific immune proteins, members of the major histocompatibility complex class I (MHCI). MHCI is expressed at the developing NMJ, and three different methods of reducing MHCI function all disrupt synapse elimination during the second postnatal week, leaving some muscle fibers multiply-innervated, despite otherwise outwardly normal synapse formation and maturation. Conversely, overexpressing MHCI modestly accelerates developmental synapse elimination. MHCI levels at the NMJ rise with aging, and reducing MHCI levels ameliorates muscle denervation in aged mice. These findings identify an unexpected role for MHCI in the elimination of neuromuscular synapses during development, and indicate that reducing MHCI levels can preserve youthful innervation of aging muscle.
Retrograde response in axotomized motoneurons: Nitric oxide as a key player in triggering reversion toward a dedifferentiated phenotype
2014, Neuroscience
Citation Excerpt :
An intriguing aspect regarding synaptic stripping of injured motoneurons concerns the origin and identity of the signaling events that promote this response. There is evidence that elimination of redundant, supernumerary, or inefficient synapses during early development is driven, at least in part, by retrograde signaling from the postsynaptic cell (for review see Nguyen and Lichtman, 1996; Goda and Davis, 2003). Following peripheral damage of motor axons, the only CNS element directly affected by the injury is the axotomized motoneuron.
The adult brain retains a considerable capacity to functionally reorganize its circuits, which mainly relies on the prevalence of three basic processes that confer plastic potential: synaptic plasticity, plastic changes in intrinsic excitability and, in certain central nervous system (CNS) regions, also neurogenesis. Experimental models of peripheral nerve injury have provided a useful paradigm for studying injury-induced mechanisms of central plasticity. In particular, axotomy of somatic motoneurons triggers a robust retrograde reaction in the CNS, characterized by the expression of plastic changes affecting motoneurons, their synaptic inputs and surrounding glia. Axotomized motoneurons undergo a reprograming of their gene expression and biosynthetic machineries which produce cell components required for axonal regrowth and lead them to resume a functionally dedifferentiated phenotype characterized by the removal of afferent synaptic contacts, atrophy of dendritic arbors and an enhanced somato-dendritic excitability. Although experimental research has provided valuable clues to unravel many basic aspects of this central response, we are still lacking detailed information on the cellular/molecular mechanisms underlying its expression. It becomes clear, however, that the state-switch must be orchestrated by motoneuron-derived signals produced under the direction of the re-activated growth program. Our group has identified the highly reactive gas nitric oxide (NO) as one of these signals, by providing robust evidence for its key role to induce synapse elimination and increases in intrinsic excitability following motor axon damage. We have elucidated operational principles of the NO-triggered downstream transduction pathways mediating each of these changes. Our findings further demonstrate that de novo NO synthesis is not only “necessary” but also “sufficient” to promote the expression of at least some of the features that reflect reversion toward a dedifferentiated state in axotomized adult motoneurons.
Plum, an immunoglobulin superfamily protein, regulates axon pruning by facilitating TGF-β signaling
2013, Neuron
Citation Excerpt :
Because MB γ axon pruning is not essential for viability, this third experiment indicates that Plum interacts with Myo in a more general context, beyond MB axon pruning. At the mammalian neuromuscular junction (NMJ), the mature pattern of connectivity is achieved via a general process of synaptic refinement that eliminates weak connections and prevents improper ones (Nguyen and Lichtman, 1996). At the fly larval NMJ, developmental synaptic refinement also occurs to produce normal neuromuscular connectivity.
Axon pruning during development is essential for proper wiring of the mature nervous system, but its regulation remains poorly understood. We have identified an immunoglobulin superfamily (IgSF) transmembrane protein, Plum, that is cell autonomously required for axon pruning of mushroom body (MB) γ neurons and for ectopic synapse refinement at the developing neuromuscular junction in Drosophila. Plum promotes MB γ neuron axon pruning by regulating the expression of Ecdysone Receptor-B1, a key initiator of axon pruning. Genetic analyses indicate that Plum acts to facilitate signaling of Myoglianin, a glial-derived TGF-β, on MB γ neurons upstream of the type-I TGF-β receptor Baboon. Myoglianin, Baboon, and Ecdysone Receptor-B1 are also required for neuromuscular junction ectopic synapse refinement. Our study highlights both IgSF proteins and TGF-β facilitation as key promoters of developmental axon elimination and demonstrates a mechanistic conservation between MB axon pruning during metamorphosis and the refinement of ectopic larval neuromuscular connections.
Recovery of whisking function after manual stimulation of denervated vibrissal muscles requires brain-derived neurotrophic factor and its receptor tyrosine kinase B
2010, Neuroscience
Citation Excerpt :
At the functional level, application of BDNF improves recovery of motor nerve function after root avulsion (Haninec et al., 2004). Furthermore, injection of BDNF into developing skeletal muscle in vivo delays synapse elimination (Nguyen and Lichtman, 1996). The above studies showing that exogenous BDNF improves both anatomical and functional outcome are supported by the current report which demonstrates that, when BDNF is insufficient, outcome is compromised to the extent that MS has no beneficial effect.
Functional recovery following facial nerve injury is poor. Neuromuscular junctions (NMJs) are “bridged” by terminal Schwann cells and numerous regenerating axonal sprouts. We have shown that this poly-innervation of NMJs can be reduced by manual stimulation (MS) with restoration of whisking function. In addition, we have recently reported that insulin-like growth factor-1 (IGF-1) is required to mediate the beneficial effects of MS. Here we extend our findings to brain derived neurotrophic factor (BDNF). We then examined the effect of MS after facial-facial anastomosis (FFA) in heterozygous mice deficient in BDNF (BDNF^+/−) or in its receptor TrkB (TrkB^+/−). We quantified vibrissal motor performance and the percentage of NMJ bridged by S100-positive terminal Schwann cells. In intact BDNF^+/− or TrkB^+/− mice and their wild type (WT) littermates, there were no differences in vibrissal whisking nor in the percentage of bridged NMJ (0% in each genotype). After FFA and handling alone (i.e. no MS) in WT animals, vibrissal whisking amplitude was reduced (60% lower than intact) and the percentage of bridged NMJ increased (27% more than intact). MS improved both the amplitude of vibrissal whisking (not significantly different from intact) and the percentage of bridged NMJ (11% more than intact). After FFA and handling in BDNF^+/− or TrkB^+/− mice, whisking amplitude was again reduced (53% and 60% lower than intact) and proportion of bridged NMJ increased (24% and 29% more than intact). However, MS failed to improve outcome in both heterozygous strains (whisking amplitude 55% and 58% lower than intact; proportion of bridged NMJ 27% and 18% more than intact). We conclude that BDNF and TRkB are required to mediate the effects of MS on target muscle reinnervation and recovery of whisking function.
Dendritic Spines: Synaptogenesis and Synaptic Pruning for the Developmental Organization of Brain Circuits
2023, Advances in Neurobiology

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Mechanism of synapse disassembly at the developing neuromuscular junction

Abstract

Neuron

Dev Biol

Dev Biol

Semin Dev Biol

Trends Neurosci

Science

Nature

Dev Biol

Rev Neurol (Paris)

Neuron

J Physiol (Lond)

J Cell Biol

Nature

Elimination of synapses in the developing nervous system

Science

Rearrangement of neuronal connections

Neuromuscular transmission in newborn rats

J Physiol (Lond)

In vivo observations of pre- and postsynaptic changes during the transition from multiple to single innervation at developing neuromuscular junctions

J Neurosci

In vivo visualization of pre- and postsynaptic changes during synapse elimination in reinnervated mouse muscle

J Neurosci

Ultrastructural evidence for axon retraction during the spontaneous elimination of polyneural innervation of the rat soleus muscle

J Neurocytol

Postnatal development of motor nerve terminais in ‘slow-red’ and ‘fast-white’ cat muscles

Acta Neurol Scand

In vivo visualization of the growth of pre- and postsynaptic elements of neuromuscular junctions in the mouse

J Neurosci

Observations on the elimination of polyneuronal innervation in developing mammalian skeletal muscle

J Physiol (Lond)

Synapse elimination in neonatal rat muscle is sensitive to pattern of muscle use

Nature

Synapse elimination from the mouse neuromuscular junction in vitro: a non-Hebbian activity-dependent process

J Neurobiol

Activity and synapse elimination at the neuromuscular junction

Cell Mol Neurobiol

Nerve and muscle development in paralyse mutant mice

Dev Biol

Multiple innervation of tonic endplates revealed by activity-dependent uptake of fluorescent probes

Nature

Properties of motor units in the transversus abdominis muscle of the garter snake

J Physiol (Lond)

Synaptic dynamics at the neuromuscular junction: mechanisms and models

J Neurobiol

Cartels, competition and activity-dependent synapse elimination

Trends Neurosci

The effect of selective, chronic stimulation on motor unit size in developing rat muscle

J Neurosci

Motor unit size and synaptic competition in rat lumbrical muscles reinnervated by active and inactive motor axons

J Physiol (Lond)

Competition favoring inactive over active motor neurons during synapse elimination

Nature

Differential loss of neuromuscular connections according to activity level and spinal position of neonatal rabbit soleus motor neurons

J Neurosci