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PubMed1978

Ultrastructural features of neuromuscular junctions in the stapedius muscle of gallus gallus.

The ultrastructure of neuromuscular junctions in the twitch fibers of the stapedius muscle of Gallus gallus (domesticus) was investigated as part of a series of neurophysiological studies. Among the morphological features observed were elongated end-plates with numerous large and clear synaptic vesicles mixed with larger dense core vesicles and irregular or aperiodic "active sites" in the presynaptic membrane where synaptic vesicles were focused. The most remarkable features of these junctions were large synaptic clefts (50-80 nm) and the absence of junctional folds in the sarcolemmal surface. Unlike the large periodic junctional folds seen in the neuromuscular junctions of frogs and in the fast twitch fibers of the mammalian stapedius, the preparations studied only show small aperiodic invaginations (primitive folds) in the postsynaptic membranes. This morphological feature remains essentially constant from newly hatched to adult chickens. While these smooth junctions are consistent with earlier findings of inconspicuous junctional folds in the twitch fibers of the chicken posterior latissimus dorsi they are unlike those seen in the fast twitch fibers of the mammalian stapedius muscle, or other twitch fibers in general. The morphological findings of the present study may also suggest that the simple, unmodified neuromuscular junctions in the stapedius of Gallus may be a useful preparation for studies of synaptic membrane structures that employ the freeze-fracture technique.

Animals↗

PubMed1977

Muscle fiber hypotrophy with intact neuromuscular junctions. A study of a patient with congenital neuromuscular disease and ophthalmoplegia.

An infant born with severe but nonprogressive somatic and cranial muscle weakness including bilateral external ophthalmoplegia was studied with a motor-point muscle biopsy. There was a strinking generalized decrease in the size of muscle fibers (hypotrophy), most marked in the type I fibers. Many of the small fibers were immature, resembling myotubes. Neuromuscular junctions on severely hypotrophic fibers were normal with esterase staining and by ultrastructural criteria. Although these are unusual clinical and biopsy characteristics, this infant's condition bears a resemblance to two other congenital nonprogressive neuromuscular diseases:myotubular myopathy and congenital fiber type disproportion. In these conditions and in our patient, there is no primary degenerative process affecting nerve or muscle but, rather, an apparent lack of maturation of fetal muscle fibers, indicating a defective normal trophic interaction between nerve and muscle.

Biopsy↗

PubMed1996

The effects of Duvernoy's gland secretion from the xenodontine colubrid Philodryas olfersii on striated muscle and the neuromuscular junction: partial characterization of a neuromuscular fraction.

The effect of Philodryas olfersii Duvernoy's secretion was studied in vivo in mice and chicks as well as in the mouse phrenic nerve-diaphragm and the chick biventer cervicis preparations. The whole secretion (20-40 micrograms/ml) increased the creatine kinase (CK) levels in mice but had no effect on the mouse phrenic nerve-diaphragm preparation. In the chick, the secretion caused head drop and paresia as well as irreversible blockade of the twitch-tension evoked by indirect stimulation in the chick biventer cervicis preparation (50% paralysis in 34.5 +/- 2.7 min, n = 4). The secretion also caused muscle contracture (30% of the maximal twitch-tension generated) after a latency of nearly 9 min. Following fractionation on a Superose 12 FPLC column, the neuromuscular activity was recovered in the high mol. wt fraction (Peak I). At a concentration of 10 micrograms/ml in the chick biventer cervicis preparation, Peak I caused 50% paralysis within 18.5 +/- 3.0 min (n = 4), and evoked a strong contracture (70% of the maximal twitch-tension generated). The contractile responses of the chick preparation to ACh and KCL were partially blocked (90%) by the whole secretion and totally blocked by Peak I. CK release was increased by the whole secretion but not by Peak I. The whole secretion also produced various degrees of muscle cell lysis and extensive widening of the intercellular spaces. The latter showed a loosely arranged membranous network. In general, Peak I caused only minor morphological alterations compared with the whole secretion, although these were still significantly different from those observed in the control preparations. The changes principally involved hypercontraction of the muscle fibers. Based on the above results, we conclude that Peak I contains the factor(s) responsible for the in vitro effects on neuromuscular transmission, whereas the direct myotoxic effect is apparently caused by at least one other component of the Duvernoy's secretion.

Animals↗

PubMed2001

Differentiation of glial cells and motor neurons during the formation of neuromuscular junctions in cocultures of rat spinal cord explant and human muscle.

Motor axons extending from embryonic rat spinal cord explants form fully mature neuromuscular junctions with cocultured human muscle. This degree of maturation is not observed in muscle innervated by dissociated motor neurons. Glial cells present in the spinal cord explants seem to be, besides remaining interneurons, the major difference between the two culture systems. In light of this observation and the well documented role of glia in neuronal development, it can be hypothesized that differentiated and long-lived neuromuscular junctions form in vitro only if their formation is accompanied by codifferentiation of neuronal and glial cells and if this codifferentiation follows the spatial and temporal pattern observed in vivo. Investigation of this hypothesis necessitates the characterization of neuronal and glial cell development in spinal cord explant-muscle cocultures. No such study has been reported, although these cocultures have been used in numerous studies of neuromuscular junction formation. The aim of this work was therefore to investigate the temporal relationship between neuromuscular junction formation and the differentiation of neuronal and glial cells during the first 3 weeks of coculture, when formation and development of the neuromuscular junction occurs in vitro. The expression of stage-specific markers of neuronal and glial differentiation in these cocultures was characterized by immunocytochemical and biochemical analyses. Differentiation of astrocytes, Schwann cells, and oligodendrocytes proceeded in concert with the differentiation of motor neurons and neuromuscular junction formation. The temporal coincidence between maturation of the neuromuscular junction and lineage progression of neurons and glial cells was similar to that observed in vivo. These findings support the hypothesis that glial cells are a major contributor to maturity of the neuromuscular junction formed in vitro in spinal cord explant-muscle cocultures.

ATP-Binding Cassette Transporters↗

PubMed1984

Inhibitory actions of vecuronium bromide on acetylcholine and glutamate responses at the frog and crayfish neuromuscular junction.

Effects of vecuronium bromide, an analog of pancuronium, on the cholinergic and glutamatergic neuromuscular junction were investigated. Vecuronium depressed the postsynaptic response of the frog end-plate at lower concentrations than 10(-6) g/ml without affecting the presynaptic events. Vecuronium decreased the amplitude of the double ACh potential, but the second potential was more markedly reduced than the first. In analogy with d-tubocurarine, this suggests that vecuronium may act in part as an open channel blocker at the frog end-plate. Vecuronium depressed both the glutamate response and the excitatory junctional potential at the crayfish neuromuscular junction, although high concentrations were required. The drug increased the decay rate of extracellularly recorded excitatory junctional potentials at the crayfish neuromuscular junction. The reduction of the crayfish synaptic response caused by vecuronium can be explained by the open channel blocking action at this junctional site. The problem that cholinergic antagonists possess a property of channel blocking at the other transmitter system was discussed.

Acetylcholine↗

PubMed1984

Presynaptic effect of streptomycin on the insect neuromuscular junction.

The effect of streptomycin on the neuromuscular junction of the cockroach leg muscle was studied by means of intracellular electrodes. The miniature excitatory postsynaptic potential (MEPSP) frequency decreased in the presence of 1 mM streptomycin. Double logarithmic plots of the quantal content against the external calcium concentration in the absence and presence of streptomycin suggested the competition for a common site of presynaptic membrane at insect neuromuscular junctions.

Animals↗

PubMed1986

Effects of aminoglycoside antibiotics on the neuromuscular junction: Part I.

The effects of aminoglycoside antibiotics (AGA) including streptomycin (SM), kanamycin (KM), gentamicin (GM), dibekacin (DKB), amikacin (AMK) and sisomycin (SISO), on the neuromuscular junction were studied by in vivo and in vitro experiments. In in vitro experiments, no effect of AGA on rat phrenic nerve diaphragm preparations was observed, but the use of the antibiotics at a high concentration exerted a slight blocking effect on the neuromuscular junction. The blocking effect of SISO and DKB on the neuromuscular junction was marked. These antibiotics were definitely found to compete with eserine in terms of the blocking effect on the neuromuscular junction, but did not compete with calcium chloride. In in vitro experiments with frog sciatic nerve and musculus sartorius preparations, DKB and SISO exerted a blocking effect on the NMJ, inducing the disappearance of action potentials and the appearance of endplate potentials (EPPs). In in vitro experiments with the preparations from Rana catesbiana frogs, SM, GM, DKB and SISO exhibited an inhibiting effect on the release of acetylcholine (ACh), a chemical neurotransmitter in neuromuscular junction, resulting in a decrease in the frequency of miniature endplate potentials (mEPPS). In in vivo experiments with rabbit sciatic tibialis anterior muscle preparations, SM, GM, DKB and SISO exerted a blocking effect on the neuromuscular junction. From the facts that the effect was augmented by the use of magnesium chloride combined with these antibiotics and that the antibiotics competed with calcium chloride and potassium chloride in terms of the blocking effect on the neuromuscular junction, the effects seemed to be due to the inhibition of ACh release.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1989

The use of gold chloride to stain developing and adult neuromuscular junctions in the insect.

Individual insect muscle fibers, whose neuromuscular junctions have been stained with a modification of Ranvier's gold chloride method, can be dissected free and mounted whole if the muscle is prefixed in aldehydes. The neuromuscular junctions along the length of the individual fibers are well delineated and can be measured and counted. Effective procedures include fixation with glutaraldehyde buffered to low pH with sodium citrate, or glutaraldehyde and paraformaldehyde combined in phosphate buffer at neutral pH, followed by exposure to citric acid and to gold chloride. The method is convenient, and could be useful for the study of arthropod neuromuscular junctions in general, since their nerve terminals do not release acetylcholine as a transmitter and cannot be stained by the more commonly used cholinesterase methods.

Animals↗

PubMed2003

Microscopic changes at the neuromuscular junction in free muscle transfer.

Free muscle transfers do not generate the same force after transfer as that at the original sites. Light and electron microscopy were used to study serially during 30 weeks the changes at the neuromuscular junction after free muscle transfer of the gracilis muscle in the adult Wistar rat. Under light microscopy, after staining with acetylthiocholine the neuromuscular junction showed changes of degeneration with withdrawal of the innervating axon terminal followed by regeneration and reconstitution of the neuromuscular junction. The newly formed neuromuscular junction still lacked the structural detail seen in the control neuromuscular junction, even after 30 weeks. With the electron microscope, mitochondrial swelling and clumping of the synaptic vesicles were followed by withdrawal of the axon terminal from the muscle membrane on denervation. The infolding of the muscle membrane at the neuromuscular junction became less prominent. With reinnervation the ultrastructure of the junction was only partially reestablished with poorly reconstituted primary and secondary folds of the muscle membrane 30 weeks after the transfer. Failure of complete reformation of the ultrastructure of the neuromuscular junction may provide another explanation for failure of full recovery of skeletal muscle function after free muscle transfer.

Animals↗

PubMed1994

Factors governing the appearance of small-mode miniature endplate currents at the snake neuromuscular junction.

At the snake neuromuscular junction, following a short period of high frequency motor nerve stimulation, a population of 'small-mode' miniature endplate currents (MEPCs) is seen. These small-mode MEPCs are believed to be due to the release of acetylcholine from incompletely refilled recycling synaptic vesicles [Searl et al., Neuroscience, 35 (1991) 145-156]. This study determines the role of the trans-vesicular membrane proton gradient in the generation of small-mode MEPCs. Preserving the trans-vesicular membrane proton gradient during synaptic vesicle exocytosis by exposure of snake nerve/muscle preparations to an extracellular pH approximately equal to the intravesicular pH, leads to an augmentation of the amplitude of the stimulation-induced small-mode MEPCs. Conversely, pretreatment of snake neuromuscular preparations with 10 mM ammonium ions, to buffer intravesicular protons and hence dissipate the trans-vesicular membrane proton gradient, leads to an inhibition of the stimulation-induced appearance of small-mode MEPCs. The data are consistent with the theory that the reduced acetylcholine content of recycled synaptic vesicles in the snake is a consequence of an incomplete restoration of the trans-vesicular membrane proton gradient following synaptic vesicle exocytosis. Thus, in recycling synaptic vesicles the limiting step in the refilling process appears to be generation of the trans-membrane proton gradient and not the transport of acetylcholine into the vesicle.

Ammonium Chloride↗

PubMed2003

Three-dimensional reconstruction of immunolabeled neuromuscular junctions in the human thyroarytenoid muscle.

OBJECTIVES/HYPOTHESIS: The objective was to reveal the location of the neuromuscular junctions in a three-dimensional reconstruction of the human thyroarytenoid muscle within the true vocal fold. STUDY DESIGN: Immunohistochemical analysis of serially sectioned human true vocal folds was performed, followed by reconstruction in three dimensions using computer imaging software. METHODS: Six fresh human larynges from autopsy were harvested, fixed in formalin, and embedded in paraffin. Eight vocal cords were studied from these six larynges. Five-micron serial sections were collected throughout the entire vocal cord in an axial plane at 500-microm intervals. Immunohistochemical analysis was performed with anti-synaptophysin antibody. A computer-controlled imaging and reconstruction system was used to create a three-dimensional reconstruction from the serial sections and to represent the location of the clustered band of neuromuscular junctions within each true vocal fold. The vocal cord was divided into equal thirds from anterior to posterior for statistical analysis. RESULTS: The most neuromuscular junctions (74%) were located in the middle third, and the least (7%) were found in the anterior third. The difference in anterior-to-posterior distribution was statistically significant in all eight specimens by chi2 analysis (P <.001). CONCLUSION: The distribution of neuromuscular junctions is not random within the human thyroarytenoid muscle. Because neuromuscular junctions are most highly concentrated in a band within the mid belly of the muscle, botulinum toxin type A (Botox) injection in patients with spasmodic dysphonia should be targeted to this region.

Adult↗

PubMed1975

The effects of diethyl ether, enflurane, and isoflurane at the neuromuscular junction.

The actions of diethyl ether, enflurane, and isoflurane at the neuromuscular junction were examined in isolated guinea pig lumbrical muscles. These anesthetics depressed the ability of carbachol to depolarize the endplate region; this depression of depolarization did not show competitive kinetics. None of the anesthetics altered the affinity of the acetylcholine receptor for d-tubocurarine, i.e., the dissociation constant of d-tubocurarine was unchanged. Since diethyl ether, enflurane, and isoflurane produced no observable alteration of the receptor, the antagonism of the drug-induced depolarization of the neuromuscular junction appears to be exerted at a stage subsequent to reaction with the receptor. (Key words: Anesthetics, volatile, diethyl ethers; Anesthetics, volatile, euflurane; Anesthetics, volatile, isoflurane; Neuromuscular relaxants, d-tubocurarine; Neuromuscular junction.).

Acetylcholine↗

PubMed1979

Frequency sweep analysis of neuromuscular junction continuity.

A new technique for measuring neuromuscular junction continuity is described. Junctional transmission is evaluated by integration of the electromyographic (EMG) response induced by intramuscular electrical stimulation. The unique characteristics of this monitoring technique are the use of intramuscular stimulation and a varying stimulation rate. The stimulus frequency is made to increase exponentially from 1 to 100 pulses per second over a period of 10 or 15 seconds. Thin coiled wire electrodes are used for stimulation and recording of the EMG response. The frequency sweep electromyogram (FS-EMB) response was measured in uncurarized and curarized tibialis anterior muscle of cat. In the uncurarized preparation, the FS-EMG response was only slightly decreased with an increasing stimulus frequency. During neuromuscular blockade with d-tubocurarine the FS-EMG response diminished with increasing frequency. The response failed at successively lower frequencies during deeper levels of neuromuscular block. Recovery proceeded in the reverse order. The frequency sweep technique provides quantitative assessment of neuromuscular junction continuity over a broad spectrum of driving frequencies without inducing fatigue. This method does not require force measurements nor voluntary effort. Intramuscular stimulation minimises painful stimuli thus making the frequency sweep technique suitable for evaluating neuromuscular transmission in either conscious or unconscious individuals.

Action Potentials↗

PubMed1988

Disruption of active zones in frog neuromuscular junctions following treatment with proteolytic enzymes.

Frog neuromuscular junction treated with proteolytic enzymes to remove the basal lamina were studied with freeze-fracture techniques in order to examine the influence of the basal lamina in the maintenance of active zone ultrastructure. The active zone is believed to be the site of transmitter release and has a unique membrane organization and location in the neuromuscular junction. After removal of the basal lamina by successive treatment of 0.01% collagenase and 0.1% protease for 1 h each, active zone disruption was observed. Some active zones became segmented, and some were also randomly located and oriented, but they still had normal double-row particle organization. Others contained only clusters of large intramembrane particles. These disorganized active zones were still functional as indicated by the presence of vesicle openings. Some enzyme-treated junctions were also exposed to the membrane cholesterol probe, filipin, to examine the expression of membrane lipid heterogeneity in disrupted active zones. As in normal active zones, filipin-sterol complexes were absent. The densities of background particles in the presynaptic membranes and of large particles thought to be acetylcholine receptors were not significantly altered by the enzyme treatment. Although a direct effect of the enzymes on active zone ultrastructure can not be totally excluded, the present work is consistent with a maintenance role of the basal lamina in active zone organization and location.

Animals↗

PubMedDate not supplied

General and strain-specific age changes at mouse limb neuromuscular junctions.

Age changes at limb neuromuscular junctions (NMJs) of CB57 and BALB/C mice were investigated and compared with previous results in a hybrid strain, in order to identify common characteristics of neuromuscular transmission and to assess the prevalence of signs of denervation and disuse. Resting membrane potential decreased with age in soleus muscles with no change in passive membrane properties. Miniature end-plate potential, amplitude and quantal content were greatly increased, with no change in muscle fiber diameter or nerve terminal morphometry. The various observed patterns of age changes were not those of disuse or denervation. Although there were diverse age changes in spontaneous transmitter release in different mouse strains, increased transmitter release per unit length of nerve terminal in limb muscle was a notably consistent finding across strains. It is apparently less subject to epigenetic variation during aging than most other reported neuromuscular physiological parameters.

Acetylcholinesterase↗

PubMed1985

Comparison of the action of types A and F botulinum toxin at the rat neuromuscular junction.

Blockade of neuromuscular transmission was produced in the lower hind limb of the rat by local injection of either type A or type F botulinum toxin (BoTx). At 1, 3, 7, and 10 days after injection, the extensor digitorum longus (edl) nerve-muscle preparation was excised and analyzed for alterations in muscle mechanical properties or spontaneous and nerve stimulus-evoked quantal transmitter release. Muscles receiving type A toxin were paralyzed up to and including 7 days after injection. Muscles treated with type F toxin, although completely paralyzed at 1 and 3 days after injection, twitched in response to nerve stimulation by 7 days. Both toxins induced a marked decrease in the frequency of miniature end-plate potentials, but type A did so to a greater extent. Between 1 and 3 days after toxin injection nerve impulse-evoked transmitter release was reduced in both type A- and type F-treated muscles. Evoked release was temperature sensitive in type A-treated muscles but not in those treated with type F. 3,4-Diaminopyridine (3,4-DAP), a compound which increases nerve-evoked transmitter release by increasing Ca2+ influx, was more effective in reversing the paralysis in type A than in type F-treated muscles. 3,4-DAP induced asynchronous end-plate potentials in response to nerve stimulation in type F-paralyzed muscles, but not in muscles treated with type A. Amidination of the amino groups (presumably lysine) on the toxin by treatment with ethylacetimidate increased the potency and efficacy of only type F BoTx. The results show that type F BoTx differs from type A, mainly by its lower potency, efficacy, shorter duration of action, and by being less effectively antagonized by 3,4-DAP.

4-Aminopyridine↗

PubMed1983

Different effects of types A and B botulinum toxin on transmitter release at the rat neuromuscular junction.

Blockade of neuromuscular transmission was produced in the lower hind limb of the rat by local injection of either crystalline type A botulinum toxin or purified type B botulinum neurotoxin. At 1, 3, 5 and 7 days after injection, the extensor digitorum longus nerve-muscle preparation was excised and analyzed in vitro for alterations in spontaneous and nerve stimulus-evoked quantal transmitter release. Muscles receiving type A toxin were paralyzed up to and including 7 days after injection. Muscles treated with type B toxin, although completely paralyzed at 1 and 3 days, twitched in response to nerve stimulation at 5 and 7 days after injection. Both toxins induced a marked decrease in the frequency of miniature endplate potentials but type A did so to a greater extent. The remaining population of miniature endplate potentials contained a greater frequency of potentials with small or large amplitudes and prolonged rise times compared to normal muscle. These changes were more pronounced with type A toxin than with type B toxin. In the presence of alpha-dinitrophenol (1 mM), high frequency, fast-rising miniature endplate potentials of uniform size reappeared. High K+ (20 mM) was less effective in this respect. At 3 days after toxin injection nerve impulse evoked transmitter release was reduced more for type A treated muscles than for type B. However, 3,4-diaminopyridine, an agent which increases nerve-evoked transmitter release by increasing Ca2+ influx, was more effective in reversing the paralysis in type A than in type B-treated muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminopyridine↗

PubMedDate not supplied

Pathology of the neuromuscular junction.

Diagnosis of neuromuscular disease by the study of motor endplate structure in the light and electron microscopes is probably one of the most specialized examinations in the field of neuropathology. The classical means of staining endplates using gold, silver or methylene blue are described as well as more modern techniques suitable for light microscopy. Specific abnormalities in patterns of terminal innervation after methylene blue staining are noted. Techniques for localizing endplates suitable for electron microscopic study are given and some of the typical changes that occur in endplate structure in some neuromuscular diseases are indicated.

Biopsy↗