Remodelling of the neuromuscular junction after subtotal disuse (original) (raw)
The European journal of neuroscience, 2015
Motor axons in peripheral nerves have the capacity to regenerate after injury. However, full functional motor recovery rarely occurs clinically, and this depends on the nature and location of the injury. Recent preclinical findings suggest that there may be a time after nerve injury where, while regrowth to the muscle successfully occurs, there is nevertheless a failure to re-establish motor function, suggesting a possible critical period for synapse reformation. We have now examined the temporal and anatomical determinants for the re-establishment of motor function after prolonged neuromuscular junction (NMJ) denervation in rats and mice. Using both sciatic transection-resuture and multiple nerve crush models in rats and mice to produce prolonged delays in reinnervation, we show that regenerating fibres reach motor endplates and anatomically fully reform the NMJ even after extended periods of denervation. However, in spite of this remarkably successful anatomical regeneration, afte...
Maturation and Maintenance of the Neuromuscular Synapse
Neuron, 2000
Dystrophin was identified as the cytoskeletal protein product of the gene mutated in Duchenne and Becker muscular dystrophies . Subsequently, dystrophin was shown to be a major component of a multimolecular membrane-associated complex, the ). The DGC includes dystrophin or its homolog, utrophin; three groups of St. Louis, Missouri 63110 ‡ Howard Hughes Medical Institute transmembrane proteins (dystroglycans [DGs], sarcoglycans, and sarcospan); and two groups of soluble pro-Departments of Physiology and Biophysics and of Neurology teins, the dystrobrevins and syntrophins. The DGC links the cytoskeleton to the extracellular matrix; cytoskeletal University of Iowa College of Medicine Iowa City, Iowa 52242 actin binds to dystrophin, which binds to -DG in the membrane, and the extracellular domain of -DG interacts with ␣-DG, which in turn binds to laminin ␣2 in the basal lamina. This complex is required for muscle stability, Summary as demonstrated by the findings that mutations in dystrophin, laminin ␣2, or any of four sarcoglycan genes all The dystrophin-glycoprotein complex (DGC) links the lead to muscular dystrophies (reviewed by Tinsley et al., cytoskeleton of muscle fibers to their extracellular ma-1994; Straub and Campbell, 1997; Ozawa et al., 1998).
Differential muscle-driven synaptic remodeling in the neuromuscular junction after denervation
2010
We used knock-in mice that express green fluorescent protein (GFP)-labeled embryonic-type acetylcholine receptors to investigate postsynaptic responses to denervation of fast-twitch and slow-twitch muscle fibers, and to visualize the integration of newly synthesized GFP-labeled embryonic-type receptors into adult synapses. The embryonic-type receptors are transiently expressed and incorporated into the denervated endplates. They replaced synaptic adult-type receptors in a directed fashion, starting from the endplate's periphery and proceeding to its central regions. The progress of embryonic-type receptor expression with respect to transcriptional control is a transient, short-term activation mechanism. The less pronounced increase in the expression levels of the GFP-labeled receptors revealed a differential shift in the integration and degradation processes that constitute the dynamic equilibrium of the synaptic receptor pool. Therefore, we were able to model the changes in the total receptor load of the neuromuscular endplate following denervation as a function of the abundance of available receptors and the initial receptor load of the endplate.
Proceedings of the National Academy of Sciences, 1977
Regenerating axons form new synapses pre- cisely at sites of original syapses in denervated skeletal muscle. To determine what role the muscle cell plays in this phenomenon, we studied reinnervation of frog muscle at intervals after crushing the nerve and damaging the muscle fibers. Damaged muscle fibers degenerate and are phagocytized, but their basement membrane persists and acts as a scaffold for regen- erating muscle cells. Specializations of the basement membrane serve to mark original synaptic sites after nerve and muscle have degenerated. Regenerating axons enter the region of damage and form functional synapses with regenerating myofibers. The new nerve terminals are found almost exclusively at the original synaptic sites, demonstrating that the integrity of the original postsynaptic cell is not necessary for topographically precise reinnervation of denervated muscle.
Journal of Neuroscience Research, 2007
Synapse competition and elimination are a general developmental process both in central and in peripheral nervous systems that is strongly activity dependent. Some common features regulate synapse competition, and one of these is an application to development of the Hebb's postulate of learning: repeated coincident spike activity in competing presynaptic inputs on the same target cell inhibits competition, whereas noncoincident activity promotes weakening of some of the inputs and ultimately their elimination. Here we report experiments that indicate that the development of muscle innervation (initial polyneuronal innervation and subsequent synapse elimination) follows the Hebb's paradigm. We utilized two different models of muscle reinnervation in the adult rat: 1) we crushed nerves going to soleus or extensor digitorum longus muscles, to activate regeneration of the presynaptic component of the neuromuscular junctions (NMJ), or 2) we injected the soleus muscle with Marcaine (a myotoxic agent) to activate regeneration of the postsynaptic component, the muscle fiber. A condition of transient polyneuronal innervation occurs during NMJ regeneration in both cases, although the two models differ insofar as the relative strength of the competing inputs is concerned. During the period of competition (a few days or weeks, in Marcaine or crush experiments, respectively), we imposed a synchronous firing pattern on the competing inputs by stimulating motor axons distal to a chronic conduction block and demonstrated that this procedure strongly inhibits synapse elimination, with respect to control muscles in which regeneration occurs under natural impulse activity of motoneurons. V V C 2006 Wiley-Liss, Inc.
The effect of lengthening contractions on neuromuscular junction structure in adult and old mice
Age (Dordrecht, Netherlands), 2016
Skeletal muscles of old mice demonstrate a profound inability to regenerate fully following damage. Such a failure could be catastrophic to older individuals where muscle loss is already evident. Degeneration and regeneration of muscle fibres following contraction-induced injury in adult and old mice are well characterised, but little is known about the accompanying changes in motor neurons and neuromuscular junctions (NMJs) following this form of injury although defective re-innervation of muscle following contraction-induced damage has been proposed to play a role in sarcopenia. This study visualised and quantified structural changes to motor neurons and NMJs in Extensor digitorum longus (EDL) muscles of adult and old Thy1-YFP transgenic mice during regeneration following contraction-induced muscle damage. Data demonstrated that the damaging contraction protocol resulted in substantial initial disruption to NMJs in muscles of adult mice, which was reversed entirely within 28 days ...
Factors that influence regeneration of the neuromuscular junction
Journal of Experimental Biology
Regeneration of neuromuscular junctions after trauma occurs in an orderly way and relies on communication between nerve and muscle. This paper summarizes evidence that factors which direct the growth and differentiation of both pre- and postsynaptic components of regenerating neuromuscular junctions are associated with the extracellular matrix of muscles.
Effects of in vivo injury on the neuromuscular junction in healthy and dystrophic muscles
The Journal of Physiology, 2013
• Strength loss induced by lengthening contractions is typically attributed to damaged force-bearing structures within skeletal muscle. Muscle lacking the structural protein dystrophin, as in Duchenne muscular dystrophy, is particularly susceptible to contractioninduced injury. • We tested the hypothesis that changes in neuromuscular junctions (NMJs) contribute to strength loss following lengthening contractions in wild-type and in dystrophic skeletal muscle. • NMJs in dystrophic (mdx) mice, the murine model of Duchenne muscular dystrophy, show discontinuous and dispersed motor end-plate morphology. Following lengthening contractions, mdx quadriceps muscles show a greater loss in force, increased neuromuscular transmission failure and decreased electromyographic measures compared to wild-type. • Consistent with NMJ disruption as a mechanism contributing to this force loss, only mdx showed increased motor end-plate discontinuity and dispersion of acetylcholine receptor aggregates. • Our results indicate that the NMJ in mdx muscle is particularly susceptible to damage, and might play a role in the exacerbated response to injury in dystrophic muscles.
Activity-dependent editing of neuromuscular synaptic connections
Brain Research Bulletin, 2000
Work over the past four decades has suggested that neural activity edits synaptic connections throughout the developing nervous system. Synaptic editing is shaped in large part by competitive interactions among different inputs innervating the same target cell that profoundly influence synaptic strength and structure. While competition plays out among presynaptic inputs that anterogradely influence their targets, postsynaptic target cells also modulate competition, in part through retrograde interactions that modulate presynaptic neurotransmitter release. One of the most useful synapses for studying how neural activity mediates synaptic editing is the connections between spinal motor neurons and skeletal muscle fibers, called neuromuscular junctions. Here we review current ideas about the role of activity in editing neuromuscular synaptic connections. The mechanisms by which activity mediates synaptic competition at these peripheral synapses are relevant to understanding how neural circuits in the central nervous system are continually altered by experience throughout life.
Muscle reinnervation—II. Sprouting, synapse formation and repression
Neuroscience, 1983
Extensor digitorum longus muscle is reinnervated by the regenerating neurites at the endplate region; as soon as the contact is made, the rate of neurite elongation inside the cleft decreases about IOOO-fold while interlibre growth and sprout formation proceed unchanged. Polyinnervation reaches the maximum level 7-10 days after reinnervation, then synaptic repression begins. The elimination of redundant innervation takes place when the biophysical properties of the muscle are again normal. There is no sign of either phagocytosis or degeneration, therefore the process of synaptic repression is probably due to retraction, as neurites do when in culture. The role of Schwann cells and nerve sheath in the process of maintenance is suggested.
Post-synaptic morphology of mouse neuromuscular junctions is linked to muscle fibre type
2020
The neuromuscular junction (NMJ) is the highly specialised peripheral synapse formed between lower motor neuron terminals and muscle fibres. Post-synaptic acetylcholine receptors (AChRs), which are found in high density in the muscle membrane, bind to acetylcholine released into the synaptic cleft of the NMJ, ultimately facilitating the conversion of motor action potentials to muscle contractions. NMJs have been studied for many years as a general model for synapse formation, development and function, and are known to be early sites of pathological changes in many neuromuscular diseases. However, information is limited on the diversity of NMJs in different muscles, whether muscle fibre type impacts NMJ morphology and growth, and the relevance of these parameters to neuropathology. Here, this crucial gap was addressed using a robust and standardised semi-automated workflow called NMJ-morph to quantify features of pre- and post-synaptic NMJ architecture in an unbiased manner. Five who...
Adaptive Remodeling of the Neuromuscular Junction with Aging
Cells
Aging is associated with gradual degeneration, in mass and function, of the neuromuscular system. This process, referred to as “sarcopenia”, is considered a disease by itself, and it has been linked to a number of other serious maladies such as type II diabetes, osteoporosis, arthritis, cardiovascular disease, and even dementia. While the molecular causes of sarcopenia remain to be fully elucidated, recent findings have implicated the neuromuscular junction (NMJ) as being an important locus in the development and progression of that malady. This synapse, which connects motor neurons to the muscle fibers that they innervate, has been found to degenerate with age, contributing both to senescent-related declines in muscle mass and function. The NMJ also shows plasticity in response to a number of neuromuscular diseases such as amyotrophic lateral sclerosis (ALS) and Lambert-Eaton myasthenic syndrome (LEMS). Here, the structural and functional degradation of the NMJ associated with agin...
Delayed synapse elimination in mouse levator palpebrae superioris muscle
The Journal of Comparative Neurology, 2011
At birth, synaptic sites in developing rodent muscles are innervated by numerous motor axons. During subsequent weeks, this multiple innervation disappears as one terminal strengthens and all the others are eliminated. Experimental perturbations that alter neuromuscular activity affect the rate of synaptic refinement with more activity accelerating the time to single innervation and neuromuscular blockade retarding it. But it remains unclear whether patterns of muscle use (driven by endogenous neuronal activity) contribute to the rate of synapse elimination. For this reason we examined the timing of supernumerary nerve terminal elimination at synapses in extraocular muscles (EOMs), a specialized set of muscles that control eye movements. On the basis of their exceptionally high patterns of activity, we hypothesized that synaptic refinement would be greatly accelerated at these synapses. We found, however, that rates of synaptic refinement were only modestly accelerated in rectus and oblique EOMs compared with synapses in somite-derived skeletal muscle. In contrast to these results, we observed a dramatic delay in the elimination of supernumerary nerve terminals from synapses in the levator palpebrae superioris (LPS) muscle, a specialized EOM that initiates and maintains eyelid elevation. In mice, natural eye-opening occurs at the end of the second postnatal week of development. Thus, while synapse elimination is occurring in most EOMs and somite-derived skeletal muscles it appears dramatically delayed in a set of specialized eyelid muscles that remain immobile during early postnatal development.
Neuroscience, 2010
The development of neuromuscular junctions exhibits profound remodeling that brings from an immature state characterized by multiple motoneuronal inputs per muscle fiber, to a mature mononeuronal innervation. This striking elimination process occurs both perinatally and during adult reinnervation, and is also widely present in the developing CNS. The accelerating influence of the amount of impulse activity on this process, has been shown by various studies, but a more subtle role of the time correlation of action potential firing in the competing inputs, has also been suggested. Here we explore the latter influence using a rat adult model of neuromuscular junction formation, that is reinnervation following a motor nerve crush. This shares all important features with perinatal development, especially the strict juxtaposition of the competing inputs. In fact the regenerating axons converge on a single cluster of postsynaptic receptors, that is the original endplate of each muscle fiber. This focus on the spatial aspect of competition between nerve endings was missing in our previous experiments employing a similar paradigm. We impose a chronic synchronous firing to the competing terminals, by in vivo electrical stimulation of their axons distal to a sciatic nerve conduction block. Control preparations, with similar post-crush reinnervation, are left with their natural impulse activity unperturbed. We find that the experimental muscles display a prolonged duration of polyneuronal innervation with respect to controls, indicating that hebbian mechanisms participate in the synapse elimination process. Another aspect dealt with in our study is the genuine nature of the polyneuronal innervation occurring during adult muscle reinnervation, because it is supported by both confocal microscopy and by appropriate electrophysiological tests that exclude electrical coupling of myofibers by gap junctions.