Juvenile and adult rat neuromuscular junctions: Density, distribution, and morphology
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Abstract Anatomical and physiological differences in neuromuscular junctions (NMJs) between juvenile and adult muscle may partially explain the variability in clinical results following chemodenervation with botulinum toxin or nerve repair in children and adults. We evaluated NMJ density, distribution, and morphometry in biceps brachii and gastrocnemius muscles from juvenile and adult rats. Motor endplates were stained with Karnovsky–Roots methods, and NMJ density (number/gram muscle tissue) was determined. The NMJ morphometry was quantitated with alpha‐bungarotoxin labeling using confocal microscopy. Juvenile rats had a greater NMJ density in both muscles compared with adult rats. Juveniles and adult rats had a similar NMJ distribution in both muscles. In juvenile muscles NMJs occupied approximately 50% of the surface area and 70% of the length, width, circumference, and gutter depth compared with adult muscles. Our study demonstrates that although NMJs are smaller, juvenile muscles have a higher NMJ density than do adult muscles with similar distributions. If these age‐dependent differences in NMJ density are obtained in humans, they may account, at least in part, for the better recovery that occurs in children than adults after nerve repair and also suggest that the dosage of botulinum toxin (units per kg) for chemodenervation may need to be increased in juveniles. © 2002 Wiley Periodicals, Inc. Muscle Nerve 26: 804–809, 2002Keywords:
Motor Endplate
Abstract 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, thereby enabling 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, how synaptic morphology changes during development, 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 wholemount muscles from wild‐type mice were dissected and compared at immature (post‐natal day, P7) and early adult (P31−32) timepoints. The inter‐muscular variability was greater in mature post‐synaptic AChR morphology than that of the pre‐synaptic motor neuron terminal. Moreover, the developing NMJ showed greater differences across muscles than the mature synapse, perhaps due to the observed distinctions in synaptic growth between muscles. Nevertheless, the amount of nerve to muscle contact was consistent, suggesting that pathological denervation can be reliably compared across different muscles in mouse models of neurodegeneration. Additionally, mature post‐synaptic endplate diameters correlated with fibre type, independently of muscle fibre diameter. Altogether, this work provides detailed information on healthy pre‐ and post‐synaptic NMJ morphology from five anatomically and functionally distinct mouse muscles, delivering useful reference data for future comparison with neuromuscular disease models.
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This protocol describes vital staining of neuromuscular junctions in the mouse triangularis sterni muscle in one incubation step, combining presynaptic, motor nerve terminal staining with the styryl dye FM1-43, which labels recycling synaptic vesicles, and TRITC-α-bungarotoxin, which labels acetylcholine receptors in the motor endplate membrane. Curr. Protoc. Mouse Biol. 1:489-496 © 2011 by John Wiley & Sons, Inc.
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Motor endplates of the interossei muscles become destabilized, whereas those of the biceps muscles remain stable in a rat model of obstetric brachial plexus palsy. However, it is unclear whether the morphology of the motor endplates of the interossei muscles is different from that of the biceps muscles in normal rat. We hypothesized that the motor endplates in the interossei muscles have specific characteristics different from those in the biceps muscles. The motor endplates were labeled with α-bungarotoxin and synaptophysin. The cross-sectional areas of the muscle fibers, the morphologies of the motor endplates, and the absolute and normalized areas (corrected by muscle fiber diameter) of the motor endplates of the interossei muscles and the biceps muscles were compared in rats at 1, 3, and 5 weeks after birth. The cross-sectional area of the interossei muscles and biceps muscle fibers were found to have increased gradually at 1, 3, and 5 weeks, but that of the biceps muscles was larger than that of the interossei muscles. The motor endplates of the interossei muscles and the biceps muscles gradually develop from crescent to pretzel shape after birth, and those of the interossei muscles have a smaller area. At 1, 3, and 5 weeks postnatally, the area of postnatal normalized motor endplates of the interossei muscles was much smaller than that of the biceps muscles. A better understanding of the morphological differences of the motor endplates between the interossei muscles and the biceps muscles may help to understand their physiological and pathological changes.
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Abstract The β-adrenergic agonists salbutamol and ephedrine have proven to be effective as therapies for human disorders of the neuromuscular junction, in particular many subsets of congenital myasthenic syndromes. However, the mechanisms underlying this clinical benefit are unknown and improved understanding of the effect of adrenergic signalling on the neuromuscular junction is essential to facilitate the development of more targeted therapies. Here, we investigated the effect of salbutamol treatment on the neuromuscular junction in the ColQ deficient mouse, a model of end-plate acetylcholinesterase deficiency. ColQ−/− mice received 7 weeks of daily salbutamol injection, and the effect on muscle strength and neuromuscular junction morphology was analysed. We show that salbutamol leads to a gradual improvement in muscle strength in ColQ−/− mice. In addition, the neuromuscular junctions of salbutamol treated mice showed significant improvements in several postsynaptic morphological defects, including increased synaptic area, acetylcholine receptor area and density, and extent of postjunctional folds. These changes occurred without alterations in skeletal muscle fibre size or type. These findings suggest that β-adrenergic agonists lead to functional benefit in the ColQ−/− mouse and to long-term structural changes at the neuromuscular junction. These effects are primarily at the postsynaptic membrane and may lead to enhanced neuromuscular transmission.
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Childers MK: Targeting the neuromuscular junction in skeletal muscles. Am J Phys Med Rehabil 2004;83(suppl):S38–S44. Botulinum neurotoxins selectively weaken skeletal muscle by presynaptic blockade of vesicles containing the neurotransmitter acetylcholine. Because the location of the neuromuscular junction (found in motor endplates) is most highly concentrated in a band within the midbelly of the muscle, injection of botulinum neurotoxins are hypothesized to be more potent when specifically targeted toward the motor endplate zones. Few studies have attempted to describe the distribution of motor endplate zones in skeletal muscles, and scant experimental data exist that directly tests this hypothesis. In this article, a rationale is presented for motor endplate targeting within specific limb muscles with respect to botulinum neurotoxin therapy.
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Relatively little is known about the development of the neuromuscular junction of extraocular muscles (EOMs). In recent years, chicks have been increasingly used as a developmental model in ophthalmological research. To utilize this model system for understanding the development and plasticity of the extraocular motor system, we investigated the structural changes that occur at the developing neuromuscular junction in the chick between embryonic day 14 (E14) and posthatch day 2 (P2). Axons and nerve terminals were visualized with fluorescent neurofilament antibodies and motor endplates with rhodamine-conjugated α-bungarotoxin. Nerve fibers and endplates were colabeled within the same tissue samples. Motor endplates (density, length, width, and area) were measured and numbers of axons per neuromuscular junction were counted using confocal and conventional microscopy. In P2 chicks, densities of motor endplates were significantly greater in the superior oblique muscle when compared with the superior rectus and lateral gastrocnemius muscle. EOMs showed a two- to threefold larger area of motor endplate size as compared to gastrocnemius muscle. Motor endplate size also differed among EOMs with the superior oblique muscle having endplates with a larger area than those of the superior rectus muscle. The period of synapse elimination was similar between EOM and gastrocnemius muscle. Synapse elimination began at about E18 and was completed by P2. By describing the normal morphological changes in developing EOMs, this study provides a baseline for future work to elucidate underlying molecular mechanisms that regulate EOM innervation and strength. © 2005 Wiley-Liss, Inc.
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