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PubMed1991

Prolonged paralysis after treatment with neuromuscular junction blocking agents.

OBJECTIVES: Previous reports have described prolonged paralysis after treatment with neuromuscular junction blocking agents in critically ill patients. The purpose of this study was to further describe a group of patients who developed prolonged weakness after treatment with these agents. DESIGN: Clinical information, electrodiagnostic and muscle pathology results are described in this group of patients. Clinical information includes diagnoses, dosage of neuromuscular junction blocker, other medications affecting the neuromuscular system, and neuromuscular examination and clinical course. SETTING: All patients were seen in the ICUs of three local hospitals. PATIENTS: Included were critically ill patients with a variety of diagnoses, all of whom developed severe weakness after discontinuation of neuromuscular junction blocking agents. INTERVENTIONS: Electrodiagnostic studies and muscle biopsies were performed on several of the patients. MEASUREMENTS AND MAIN RESULTS: All patients had pronounced weakness without sensory loss. Electrodiagnostic and muscle pathology findings were consistent with failed neuromuscular transmission. Although many patients had disorders or were taking medications that can injure the neuromuscular system, no disorder or medication was common to all. Recovery of strength often took several months and most patients were slow to wean from mechanical ventilator support. CONCLUSIONS: Although alternative explanations cannot be excluded with certainty, the use of neuromuscular junction blocking agents may lead to neurogenic atrophy and care must be taken when using them.

Biopsy↗
PubMed1983

Ultrastructural studies of neuromuscular junctions in visceral and skeletal muscles of the chaetognath Sagitta setosa.

The ultrastructural characteristics of the neuromuscular junctions were studied in oesophageal (visceral) muscle and in four skeletal muscles of the head and trunk in Sagitta. Three types of neuromuscular junctions were encountered. The first is made up of nerve terminals which synapse with the surface of the muscle fiber, in a deep or in a slight depression. The second is characterized by muscle fiber protrusions that cross the connective tissue and form synapses with nerve endings; in this type, numerous post-junctional membrane folds are noted. In the third type, the synaptic cleft is very large (greater than 0.2 micron) and contains bundles of connective fibers. Nerve endings are partially ensheathed in glial cells; they contain mostly clear synaptic vesicles, though some dense-cored vesicles are noted. In many muscle fibers post-junctional membrane thickenings are also observed. All observed neuromuscular junctions resemble chemical synapses. Chaetognaths thus show a great variety of neuromuscular junction ultrastructure as do for instance Arthropods.

Animals↗
PubMed1982

Influence of neostigmine treatment on embryonic development of acetylcholine receptors and neuromuscular junctions.

The postulated role of the acetylcholine receptor in the formation of neuromuscular synapses during the course of embryonic development was investigated in the superior oblique muscle of white Peking duck embryos. The possibility that the number of receptors could be experimentally lowered by chronic injections of the anticholinesterase agent, neostigmine methylsulfate, was determined using 125I-alpha-bungarotoxin. The total number of acetylcholine receptors on incubation day 12, 2 d subsequent to the onset of treatment, was reducted 45% as compared to saline-treated controls. A similar reduction in total receptor content (49%) was also observed on day 19. Radioautographic preparations showed that clusters of acetylcholine receptors were rare and that the grain density of extrajunctional receptors was also reduced. Hence, chronic treatment with neostigimine during development was observed to exert an effect on both the number and distribution of receptors in the developing superior oblique muscle. These changes occurred in the absence of any apparent effect on muscle differentiation in general. Myoblasts and myotubes were present on day 14 and further differentiated into myofibers by day 18 in both neostigmine and saline-treated muscles. The cytology of the develop;ing muscle cells also appeared normal. This is in contradistinction to the striking morphological changes that take place in adult mammalian and avian muscle after anticholinesterase treatment. More significantly, the decreased total receptor content and sparsity of clusters had no apparent effect on the formation of developing neuromuscular junctions at the electron microscopic level. The frequency of neuromuscular junctions in neostigmine-treated muscles was similar to that of the controls. It is concluded that acetylcholine receptor clusters are not required for the events leading to the morphological formation of neuromuscular junctions during in vivo development.

Animals↗
PubMedDate not supplied

Assembly, plasticity and selective vulnerability to disease of mouse neuromuscular junctions.

Although physiological differences among neuromuscular junctions (NMJs) have long been known, NMJs have usually been considered as one type of synapse, restricting their potential value as model systems to investigate mechanisms controlling synapse assembly and plasticity. Here we discuss recent evidence that skeletal muscles in the mouse can be subdivided into two previously unrecognized subtypes, designated FaSyn and DeSyn muscles. These muscles differ in the pattern of neuromuscular synaptogenesis during embryonic development. Differences between classes are intrinsic to the muscles, and manifest in the absence of innervation or agrin. The distinct rates of synaptogenesis in the periphery may influence processes of circuit maturation through retrograde signals. While NMJs on FaSyn and DeSyn muscles exhibit a comparable anatomical organization in postnatal mice, treatments that challenge synaptic stability result in nerve sprouting, NMJ remodeling, and ectopic synaptogenesis selectively on DeSyn muscles. This anatomical plasticity of NMJs diminishes greatly between 2 and 6 months postnatally. NMJs lacking this plasticity are lost selectively and very early on in mouse models of motoneuron disease, suggesting that disease-associated motoneuron dysfunction may fail to initiate maintenance processes at "non-plastic" NMJs. Transgenic mice overexpressing growth-promoting proteins in motoneurons exhibit greatly enhanced stimulus-induced sprouting restricted to DeSyn muscles, supporting the notion that anatomical plasticity at the NMJ is primarily controlled by processes in the postsynaptic muscle. The discovery that entire muscles in the mouse differ substantially in the anatomical plasticity of their synapses establishes NMJs as a uniquely advantageous experimental system to investigate mechanisms controlling synaptic rearrangements at defined synapses in vivo.

Animals↗
PubMed1981

Ultrastructural evidence indicating reorganization at the neuromuscular junction in the normal rat soleus muscle.

The ultrastructural organization of 40 soleus neuromuscular junctions from ten normal young adult male and female Sprague-Dawley (SD)-derived rats (Charles River Breeders, CD-Crl:COBS (SD)BR) has been studied. A smaller sample of motor endplates from the gastrocnemius, diaphragm, and extensor digitorum longus muscles of these rats as well as from the soleus muscles of two adult Wistar (W) rats (Crl:COBS(WI)BR) was included. Widespread ultrastructural reorganization was evident at the soleus neuromuscular junction during the growth period from three to five months of age. A major characteristic of reorganization is the presence of junctional folds not associated with axonal terminals; such sites occur within a single endplate adjacent to areas with typical intact synaptic associations. Additional features possibly related to remodelling are: 1) spatial separation of axonal terminals from the myofiber, 2) intervention of Schwann cell cytoplasm between an axon terminal and myofiber, 3) aggregates of satellite cells, and 4) folded or multilayered basal lamina. These features are most pronounced in the soleus muscle but occur to varying degrees in the neuromuscular junctions of other muscles of SD-derived rats. Distinctive characteristics of the rat soleus postjunctional sarcoplasm include the widespread occurrence of myofibrillar components, abundant free and membrane-associated polysomes, and triads oriented in various planes. Away from such discrete sites, myofibers possess the usual highly oriented organization of myofibrils, T tubules, sarcoplasmic reticulum, and mitochondria. The soleus muscle is a postural muscle that responds directly to rising workload imposed by continuous body growth during young adulthood by steady myofiber hypertrophy and conversion of motor units (Kugelberg, '76). This changing structural-functional relationship may be reflected also by ultrastructural remodelling of the neuromuscular junctions reported here.

Aging↗
PubMed1982

Mechanisms of acetylcholine receptor loss from the neuromuscular junction.

At the normal mammalian neuromuscular junction the half-life of the acetylcholine receptor (AChR) ranges from 6 to 13 days (estimates from seven different laboratories). Indirect evidence suggests that the internalized receptor is degraded by a lysosomal mechanism. We have now traced the fate of the AChR labelled in vivo with peroxidase-alpha-bungarotoxin. Segments of junctional folds bearing AChRs are internalized by endocytosis. The endocytosed vesicles are engulfed by tubules and larger vesicles which, by electron cytochemical criteria, represent secondary lysosomes. Pathological mechanisms increased AChR loss from the end-plate. These include destruction of junctional folds, formation of immature junctions with a few or no junctional folds, accelerated internalization of AChR, impaired membrane insertion of new AChR and, possibly decreased AChR synthesis. The common mechanism for destruction of the junctional folds is an altered subsynaptic ionic milieu, and especially focal calcium excess. This can be induced by antibody and complement, too frequent or prolonged openings of the acetylcholine (ACh)-induced ion channel, and other membrane defects. In acquired autoimmune myasthenia gravis there is (a) antibody-dependent complement-mediated lysis of the junctional folds, (b) accelerated internalization of AChR cross-linked by antibody and (c) decreased insertion of AChR into the postsynaptic membrane. The last mechanism is attributed to lack of membrane patches available for tight packing and secure anchoring of the receptor. In acute, but not in chronic, experimental autoimmune myasthenia gravis, and infrequently in human myasthenia gravis, macrophages destroy junctional folds opsonized by antibody and C3. In a recently recognized congenital syndrome attributed to a prolonged open time of the ACh-induced ion channel, and to a lesser extent in congenital end-plate acetylcholinesterase deficiency, AChR is lost with degradation of junctional folds. In other, less well-defined, congenital syndromes there is deficiency or abnormal function of AChR. This could arise from decreased synthesis or membrane insertion or accelerated degradation of AChR, or from a structurally abnormal AChR with reduced affinity for ACh or with a diminished conductance or open time of its ion channel.

Animals↗
PubMed1971

Physiological studies during formation and development of rat neuromuscular junctions in tissue culture.

Developing neuromuscular junctions in tissue cultures of rat embryo spinal cord and muscle were studied with intracellular recording. Excitatory junctional potentials (ejps) were found during nerve or spinal cord stimulation, and also arising spontaneously. The time-course of the potentials tended to be shorter in cultures older than 9 days in vitro than in more recently innervated cultures. Evidence of multiple innervation was found in many cells. In order to test the hypothesis that transmitter was released in integral multiples of a quantal amount and according to a Poisson distribution, mean quantum content was calculated from the coefficient of variation of ejp amplitudes, the percentage of zero responses, and the ratio of mean amplitude to mean of the smallest class of amplitudes. The three independent measures were in fair or good mutual agreement, implying that the mechanism of transmitter release in newly developed junctions is the same as in the adult. In newly formed junctions, ejps were subthreshold for action potential generation, but afterwards mean quantum content increased and action potentials were generated by single ejps. In fibers developing both with and without innervation, the entire muscle cell surface was as sensitive to acetylcholine as the adult end plate region. Innervation was related to cross-striation: every cross-striated fiber tested was found to be innervated, and denervation in vitro led to loss of distinct cross-striations.

Acetylcholine↗
PubMedDate not supplied

Transcription in neuromuscular junction formation: who turns on whom?

The neuromuscular junction is a particular advantageous synapse to investigate the molecular processes engaged in synaptogenesis. Both the motor nerve and the muscle cell contribute to the patterned distribution of a definite set of membrane proteins into two distinct regions, a sub-synaptic end plate zone and an extra-synaptic region. Accordingly, the transcription of acetylcholine receptors is highly compartmentalized being much higher in the sub-synaptic the in the extra-synaptic region. In this review, we focus on the signaling pathways and the gene expression mechanisms that mediate the enhanced transcription in the sub-synaptic region and the silencing of transcription in extra-synaptic regions.

Animals↗
PubMed1999

Glutamate receptor expression regulates quantal size and quantal content at the Drosophila neuromuscular junction.

At the Drosophila glutamatergic neuromuscular junction, the postsynaptic cell can regulate synaptic strength by both changing its sensitivity to neurotransmitter and generating a retrograde signal that regulates presynaptic transmitter release. To investigate the molecular mechanisms underlying these forms of plasticity, we have undertaken a genetic analysis of two postsynaptic glutamate receptors that are expressed at this synapse. Deletion of both genes results in embryonic lethality that can be rescued by transgenic expression of either receptor. Although these receptors are redundant for viability, they have important differences. By transgenically rescuing the double mutant, we have investigated the relationship of receptor gene dosage and composition to synaptic function. We find that the receptor subunit composition regulates quantal size, Argiotoxin sensitivity, and receptor desensitization kinetics. Finally, we show that the activity of the receptor can regulate the retrograde signal functioning at this synapse. Thus, the diversity of receptors expressed at this synapse provides the cell with mechanisms for generating synaptic plasticity.

Animals↗
PubMed1982

Internal and external differentiations of the postsynaptic membrane at the neuromuscular junction.

Frog, snake and rat neuromuscular junctions were prepared for electron microscopy by the quick-freeze, deep-etch, rotary replication procedure. The postsynaptic membrane was exposed by treating muscles with 1 mg/ml collagenase to remove the basal lamina. Present on the apices of the postsynaptic folds are regular arrays of 8-9 nm protrusions. These are not seen in the depths of the folds nor elsewhere on the muscle surface, thus they presumably represent the heads of cholinergic receptor molecules. These protrusions tend to be arranged in parallel rows two-abreast. Their high concentration (10 000/microns2) and their orderly arrangement is basically similar to the receptors seen in Torpedo postsynaptic membrane. Their distribution did not appear to change after denervation. Efforts were made to expose possible anchoring structures of these receptors, by treating muscles with 0.1% Saponin immediately before and/or during fixation in 1% formaldehyde, or by homogenizing muscles after brief formaldehyde fixation. This washed most soluble protein out of the cytoplasm and exposed a submembraneous meshwork just beneath the postsynaptic membrane. This meshwork appears to connect the membrane to underlying bundles of intermediate filaments which course through the postsynaptic processes that border each fold. This meshwork is presumably equivalent to the postsynaptic 'density' seen in thin sections. Its three-dimensional structure suggests that it could anchor receptor molecules to underlying cytoskeletal elements and thus immobilize receptors in the plane of the postsynaptic membrane.

Animals↗
PubMed2006

Development of the neuromuscular junction.

The differentiation of the neuromuscular junction is a multistep process requiring coordinated interactions between nerve terminals and muscle. Although innervation is not needed for muscle production, the formation of nerve-muscle contacts, intramuscular nerve branching, and neuronal survival require reciprocal signals from nerve and muscle to regulate the formation of synapses. Following the production of muscle fibers, clusters of acetylcholine receptors (AChRs) are concentrated in the central regions of the myofibers via a process termed "prepatterning". The postsynaptic protein MuSK is essential for this process activating possibly its own expression, in addition to the expression of AChR. AChR complexes (aggregated and stabilized by rapsyn) are thus prepatterned independently of neuronal signals in developing myofibers. ACh released by branching motor nerves causes AChR-induced postsynaptic potentials and positively regulates the localization and stabilization of developing synaptic contacts. These "active" contact sites may prevent AChRs clustering in non-contacted regions and counteract the establishment of additional contacts. ACh-induced signals also cause the dispersion of non-synaptic AChR clusters and possibly the removal of excess AChR. A further neuronal factor, agrin, stabilizes the accumulation of AChR at synaptic sites. Agrin released from the branching motor nerve may form a structural link specifically to the ACh-activated endplates, thereby enhancing MuSK kinase activity and AChR accumulation and preventing dispersion of postsynaptic specializations. The successful stabilization of prepatterned AChR clusters by agrin and the generation of singly innervated myofibers appear to require AChR-mediated postsynaptic potentials indicating that the differentiation of the nerve terminal proceeds only after postsynaptic specializations have formed.

Acetylcholine↗
PubMed1986

Long-term facilitation alters transmitter releasing properties at the crayfish neuromuscular junction.

Synaptic transmission at the neuromuscular junction of the excitatory axon supplying the crayfish opener muscle was examined before and after induction of long-term facilitation (LTF) by a 10-min period of stimulation at 20 Hz. Induction of LTF led to a period of enhanced synaptic transmission, which often persisted for many hours. The enhancement was entirely presynaptic in origin, since quantal unit size and time course were not altered, and quantal content of transmission (m) was increased. LTF was not associated with any persistent changes in action potential or presynaptic membrane potential recorded in the terminal region of the excitatory axon. The small muscle fibers of the walking-leg opener muscle were almost isopotential, and all quantal events could be recorded with an intracellular microelectrode. In addition, at low frequencies of stimulation, m was small. Thus it was possible to apply a binomial model of transmitter release to events recorded from individual muscle fibers and to calculate values for n (number of responding units involved in transmission) and p (probability of transmission for the population of responding units) before and after LTF. In the majority of preparations analyzed (6/10), amplitude histograms of evoked synaptic potentials could be described by a binomial distribution with a small n and moderately high p. LTF produced a significant increase in n, while p was slightly reduced. The results can be explained by a model in which the binomial parameter n represents the number of active synapses and parameter p the mean probability of release at a synapse. Provided that a pool of initially inactive synapses exists, one can postulate that LTF involves recruitment of synapses to the active state.

Action Potentials↗
PubMed2000

The effect of ammodytin L on frog neuromuscular junction.

Effects of myotoxic ammodytin L on frog neuromuscular junction were examined by morphological, enzymatic and electrophysiological studies. Electron micrographs of the frog neuromuscular junction revealed destruction of muscle fibers. Nerve terminals seemed to remain intact. The activity of the muscle specific enzymes in the bathing solution rose with time in a dose-dependent manner. Ammodytin L depressed the response of the neuromuscular preparation to acetylcholine. Measurements of electrically triggered isometric muscle contractions show that the toxin depresses the neuromuscular transmission both in the curarised and in the untreated frog neuromuscular preparation with marked difference between the time-courses of both effects, indicating that neurotoxic effect may also be involved.

Acetylcholine↗
PubMed2004

Presynaptic inhibition of spontaneous acetylcholine release induced by adenosine at the mouse neuromuscular junction.

1. At the mouse neuromuscular junction, adenosine (AD) and the A(1) agonist 2-chloro-N(6)-cyclopentyl-adenosine (CCPA) induce presynaptic inhibition of spontaneous acetylcholine (ACh) release by activation of A(1) AD receptors through a mechanism that is still unknown. To evaluate whether the inhibition is mediated by modulation of the voltage-dependent calcium channels (VDCCs) associated with tonic secretion (L- and N-type VDCCs), we measured the miniature end-plate potential (mepp) frequency in mouse diaphragm muscles. 2. Blockade of VDCCs by Cd(2+) prevented the effect of the CCPA. Nitrendipine (an L-type VDCC antagonist) but not omega-conotoxin GVIA (an N-type VDCC antagonist) blocked the action of CCPA, suggesting that the decrease in spontaneous mepp frequency by CCPA is associated with an action on L-type VDCCs only. 3. As A(1) receptors are coupled to a G(i/o) protein, we investigated whether the inhibition of PKA or the activation of PKC is involved in the presynaptic inhibition mechanism. Neither N-(2[p-bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide (H-89, a PKA inhibitor), nor 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine (H-7, a PKC antagonist), nor phorbol 12-myristate 13-acetate (PHA, a PKC activator) modified CCPA-induced presynaptic inhibition, suggesting that these second messenger pathways are not involved. 4. The effect of CCPA was eliminated by the calmodulin antagonist N-(6-aminohexil)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7) and by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid-acetoxymethyl ester epsilon6TDelta-BM, which suggests that the action of CCPA to modulate L-type VDCCs may involve Ca(2+)-calmodulin. 5. To investigate the action of CCPA on diverse degrees of nerve terminal depolarization, we studied its effect at different external K(+) concentrations. The effect of CCPA on ACh secretion evoked by 10 mm K(+) was prevented by the P/Q-type VDCC antagonist omega-agatoxin IVA. 6. CCPA failed to inhibit the increases in mepp frequency evoked by 15 and 20 mm K(+). We demonstrated that, at high K(+) concentrations, endogenous AD occupies A1 receptors, impairing the action of CCPA, since incubation with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, an A(1) receptor antagonist) and adenosine deaminase (ADA), which degrades AD into the inactive metabolite inosine, increased mepp frequency compared with that obtained in 15 and 20 mm K(+) in the absence of the drugs. Moreover, CCPA was able to induce presynaptic inhibition in the presence of ADA. It is concluded that, at high K(+) concentrations, the activation of A(1) receptors by endogenous AD prevents excessive neurotransmitter release.

Acetylcholine↗
PubMed1996

Schwann cells induce and guide sprouting and reinnervation of neuromuscular junctions.

The "terminal' Schwann cells that sit atop the neuromuscular junction sense neuromuscular transmission and respond to perturbations of this transmission by extending long processes. These processes have the ability to induce nerve growth and serve as substrates to guide this growth. These processes thus play major roles in muscle reinnervation and in sprouting. An absence of nerve sprouting is correlated with the apoptotic death of terminal Schwann cells at denervated endplates in neonatal muscles. Thus, Schwann cells appear to participate actively in the maintenance and repair of neuromuscular synapses.

Cell Communication↗
PubMed2000

Novel method for the labeling of distant neuromuscular junctions.

Essential to understanding the roles proteins and structural elements play at the synapse is to understand the development, remodeling and reinnervation of peripheral neuromuscular junctions. It has, however, been a challenging task to label and visualize neuromuscular junctions. In this paper we demonstrate how adenovirus technology can be combined with intraspinal microinjection techniques to follow both the development and the reinnervation of a distant peripheral neuromuscular junction in the rat. A recombinant adenovirus containing VAMP-2 (synaptobrevin-2) was fused to the green fluorescent protein (GFP) and microinjected into the region of the lumbar motor neurons. We were able to follow the neuronal incorporation, axonal transport and synaptic localization of the GFP-VAMP-2 using fluorescence microscopy. GFP-VAMP-2 was found in neuronal cell bodies, selected sciatic nerve axons and was concentrated in the presynaptic nerve terminal. During reinnervation of the neuromuscular junction, GFP-VAMP-2 allows us to follow the time course of junctional reinnervation. Thus, the microinjection of microliter amounts of labeled recombinant virus into locations far distant from target regions can be used to efficiently study the formation of neuromuscular junctions with a minimum of trauma to the animal.

Adenoviridae↗
PubMed1998

Modulation of vertebrate and invertebrate neuromuscular junctions.

Advances in our understanding of how the neuromuscular junction is modulated include an expanded appreciation of the many different types of modulatory influences, from soluble factors to second-messenger systems, to specific proteins in nerve and muscle. Recent studies indicate that modulation of neuromuscular function is effected on both the presynaptic and postsynaptic sides of the neuromuscular junction.

Animals↗
PubMed1995

Morphological changes of neuromuscular junctions in the dystrophic (dy) mouse: a scanning and transmission electron microscopic study.

Neuromuscular junctions in the extensor digitorum longus muscle of control and dystrophic (dy) mice at stages ranging from 30 to 120 postnatal days were examined by scanning and transmission electron microscopy (SEM and TEM). In control mice, the neuromuscular junctions consisted of thin ramifying nerve endings and of complex labyrinthine gutters with a great number of slit-like junctional folds. The subneural apparatuses of dy mice on the 30th and the 60th postnatal days were composed of undeveloped gutters or a number of cup-like depressions containing a few pit-like or slit-like junctional folds. In dystrophic neuromuscular junctions on the 120th postnatal day, subneural apparatuses were classified into two types: one had a cluster of continuous cup-like depressions with or without slit-like junctional folds, and the other consisted of discrete depressions containing slit-like junctional folds. Moreover, a small number of dystrophic muscle fibers were endowed with two subneural apparatuses which were 20 to 30 microns away from each other. Small round pits (0.5-1.0 microns in diameter) in some cup-like depressions were occasionally protruded by short processes of terminal axons. The present findings suggest that the age-dependent postsynaptic structural changes of dystrophic dy mice induce a complex morphological reorganization of presynaptic nerve endings. This might help the nerve endings compensate for the functional deterioration of dystrophic muscle fibers.

Animals↗