Synaptic current between neuromuscular junction folds

Vautrin, Jean; Mambrini, J

doi:10.1016/s0022-5193(89)80110-9

Cited by 31 publications

(31 citation statements)

References 40 publications

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“…Furthermore, we found that the overall miniature endplate current amplitudes in all four DOK7 patients were not diminished, similar to previous findings (Table 2). 24 In addition, the dispersion of endplates observed in the teased muscle fibers implies remodeling of the NMJ and supports the notion that DOK7 mutations lead to NMJ synaptopathy, as first proposed by Beeson et al2 Finally, the decrease in the fraction of type II fibers and the reduction in the complexity of postsynaptic folds both predict a reduced concentration of endplate sodium channels and an increase in the threshold level for firing muscle action potentials14, 22, 23; this can further impair the safety margin of neuromuscular transmission 10, 25…”

Section: Discussionsupporting

confidence: 73%

Variable phenotypes associated with mutations in DOK7

Anderson

Bowe

et al. 2008

Muscle and Nerve

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Many patients with the limb-girdle variant of congenital myasthenic syndrome (CMS) possess mutations in the human Dok-7 gene (DOK7). We identified six unrelated CMS patients with DOK7 mutations. Two patients, one mildly and the other moderately affected, were homozygous for the previously described 1263insC mutation. The common 1124_1127dupTGCC mutation was detected in the other four patients, whose clinical phenotypes range from mildly to severely affected. This striking phenotypic heterogeneity found both within and between mutational classes is made more compelling by data from our electrophysiological studies and electron microscopy of the neuromuscular junction (NMJ). Indeed, several aspects of the physiological and morphometric data do not correlate with genotype or severity of clinical phenotype. Overall, our study corroborates the findings of others and provides an additional demonstration of the considerable phenotypic variability associated with CMS due to DOK7 mutations.

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Section: Discussionsupporting

confidence: 73%

Variable phenotypes associated with mutations in DOK7

Anderson

Bowe

et al. 2008

Muscle and Nerve

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“…As mentioned in the Introduction, DMD model mouse NMJs have reduced postsynaptic membrane folds. This may be the most important factor underlying the MEPP amplitude reduction because one role of the folds is to increase the local cytoplasmic electrical resistance, thereby amplifying the depolarizing effect of AChR‐mediated ion current (Vautrin & Mambrini, ). However, mdx/utrn −/− NMJs have much fewer and more shallow folds than mdx (Grady et al ., ), but no extra MEPP amplitude reduction was found here.…”

Section: Discussionmentioning

confidence: 99%

Characterization of neuromuscular synapse function abnormalities in multiple Duchenne muscular dystrophy mouse models

Pijl

Putten

Niks

et al. 2016

Eur J of Neuroscience

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Duchenne muscular dystrophy (DMD) is an X-linked myopathy caused by dystrophin deficiency. Dystrophin is present intracellularly at the sarcolemma, connecting actin to the dystrophin-associated glycoprotein complex. Interestingly, it is enriched postsynaptically at the neuromuscular junction (NMJ), but its synaptic function is largely unknown. Utrophin, a dystrophin homologue, is also concentrated at the NMJ, and upregulated in DMD. It is possible that the absence of dystrophin at NMJs in DMD causes neuromuscular transmission defects that aggravate muscle weakness. We studied NMJ function in mdx mice (lacking dystrophin) and wild type mice. In addition, mdx/utrn(+/-) and mdx/utrn(-/-) mice (lacking utrophin) were used to investigate influences of utrophin levels. The three Duchenne mouse models showed muscle weakness when comparatively tested in vivo, with mdx/utrn(-/-) mice being weakest. Ex vivo muscle contraction and electrophysiological studies showed a reduced safety factor of neuromuscular transmission in all models. NMJs had ~ 40% smaller miniature endplate potential amplitudes compared with wild type, indicating postsynaptic sensitivity loss for the neurotransmitter acetylcholine. However, nerve stimulation-evoked endplate potential amplitudes were unchanged. Consequently, quantal content (i.e. the number of acetylcholine quanta released per nerve impulse) was considerably increased. Such a homeostatic compensatory increase in neurotransmitter release is also found at NMJs in myasthenia gravis, where autoantibodies reduce acetylcholine receptors. However, high-rate nerve stimulation induced exaggerated endplate potential rundown. Study of NMJ morphology showed that fragmentation of acetylcholine receptor clusters occurred in all models, being most severe in mdx/utrn(-/-) mice. Overall, we showed mild 'myasthenia-like' neuromuscular synaptic dysfunction in several Duchenne mouse models, which possibly affects muscle weakness and degeneration.

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“…This might account for much of the lowering of threshold seen when action potentials are generated by nerve-evoked endplate currents rather than by current injected from an intracellular electrode. A further possible effect of the postsynaptic geometry, suggested by Vautrin & Mambrini (1989), results from the fact that the narrow cytoplasmic cleft between the synaptic folds has an electrical resistance similar in magnitude to the input resistance of the muscle fibre. This would be expected to result in a voltage-dividing effect, reducing the magnitude of the EPP recorded by an intracellular electrode.…”

Section: Discussionmentioning

confidence: 99%

Action potential generation in rat slow‐ and fast‐twitch muscles.

Wood¹,

Slater²

1995

The Journal of Physiology

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1. In skeletal muscle fibres, voltage-gated sodium channels are concentrated at the neuromuscular junction. The effect of this accumulation of sodium channels on action potential generation was investigated in rat slow-and fast-twitch muscle fibres. 2. Intracellular microelectrodes were used to generate and record action potentials, from an imposed membrane potential of -75 and -90 mV, in junctional and extrajunctional regions of the muscle fibre. To identify junctional regions, preparations were incubated with 5 x 10-7 M d-tubocurarine (dTC) to block muscle contraction in response to nerve stimulation whilst allowing endplate potentials (EPPs) to be recorded. Injection of rectangular depolarizing current pulses initiated action potentials at the endplate with threshold values several millivolts lower than those generated elsewhere in the fibre. In addition, the maximum rate of rise of the action potential was greater at the endplate than in extrajunctional regions.3. In other muscles, neuromuscular transmission was partially blocked with dTC (2 x 10-7 M), such that repetitive nerve stimulation evoked action potentials and EPPs in the same fibre. The threshold of these nerve-evoked action potentials was approximately 50% lower than values derived from action potentials generated by current injection. 4. It is concluded that the threshold for action potential generation is significantly lower at the neuromuscular junction than in extrajunctional regions of skeletal muscle fibres. Furthermore, nerve-evoked current is more effective at generating an action potential than is injected current.

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Synaptic current between neuromuscular junction folds

Cited by 31 publications

References 40 publications

Variable phenotypes associated with mutations in DOK7

Variable phenotypes associated with mutations in DOK7

Characterization of neuromuscular synapse function abnormalities in multiple Duchenne muscular dystrophy mouse models

Action potential generation in rat slow‐ and fast‐twitch muscles.

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