Safety factor at the neuromuscular junction

Wood, Sarah; Slater, Clarke R.

doi:10.1016/s0301-0082(00)00055-1

Cited by 364 publications

(297 citation statements)

References 205 publications

Supporting

Mentioning

287

Contrasting

Unclassified

Order By: Relevance

“…However, the extent of this difference was only small (EPPs ran down to a plateau level of 79.5% of the first EPP, compared to 83.2% at WT NMJs). In view of the presence of a large safety factor in neuromuscular transmission (Wood and Slater, 2001), such a small reduction will most likely not threat successful transmission and cause muscle weakness. This was confirmed in testing the aged GM2s-KO mice with a grip strength meter, where they pulled equal forces as WT controls.…”

Section: Discussionmentioning

confidence: 99%

Neuromuscular synaptic transmission in aged ganglioside-deficient mice

Zitman

Todorov

Verschuuren

et al. 2011

Neurobiology of Aging

View full text Add to dashboard Cite

Gangliosides are sialylated glycosphingolipids that are present in high density on neuronal membranes, especially at synapses, where they are assumed to play functional or modulating roles. Mice lacking GM2/GD2-synthase express only the simple gangliosides GD3 and GM3 and develop progressive motor behaviour deficits upon ageing, apparently due to failing complex ganglioside-dependent maintenance and/or repair processes or, alternatively, toxic GM3/GD3 accumulation. We investigated the function of neuromuscular junctions (NMJs) of aged (>9 months-old) GM2/GD2-synthase null-mutant mice, because synaptic dysfunction might develop with age and could potentially contribute to the late-onset motor phenotype. In addition, we studied NMJs of old mice lacking GD3-synthase (expressing only O-and aseries gangliosides), which do not show an overt neurological phenotype but may develop subclinical synaptic deficits. Detailed electrophysiological analyses showed subtle changes in presynaptic neurotransmitter release. Acetylcholine release at 40 Hz nerve stimulation at aged GM2/GD2-synthase null-mutant NMJs ran down slightly more pronounced than at wild-type NMJs, and spontaneous acetylcholine release rate at GD3-synthase null-mutant NMJs was somewhat higher than at wild-type, selectively at 25 C bath temperature. Interestingly, we observed faster kinetics of postsynaptic electrophysiological responses at aged GD3-synthase null-mutant NMJs, not previously seen by us at NMJs of young GD3-synthase null-mutants or other types of (aged or young) ganglioside-deficient mice. These kinetic changes might reflect a change in postsynaptic acetylcholine receptor behaviour. Our data indicate that it is highly unlikely that transmission failure at NMJs contributes to the progressive motor defects of aged GM2/GD2-synthase null-mutants and that, despite some kinetic changes of synaptic signals, neuromuscular transmission remains successful in aged GD3-synthase null-mutant mice. Apparently, mutual redundancy of the different gangliosides in supporting presynaptic function, as observed previously by us in young mice, remains adequate upon ageing or, alternatively, gangliosides have only relatively little direct impact on neuromuscular synaptic function, even in aged mice. AbbreviationsACh, acetylcholine; AChR, acetylcholine receptor; EPP, endplate potential; GD3s-KO, α2,8-sialyltransferase knockout; GM2s-KO, β1,4-GalNAc-transferase knockout; MEPP, miniature endplate potential; NMJ, neuromuscular junction; WT, wild-type.Zitman et al., Synaptic function in aged ganglioside-deficient mice 3

show abstract

Section: Discussionmentioning

confidence: 99%

Neuromuscular synaptic transmission in aged ganglioside-deficient mice

Zitman

Todorov

Verschuuren

et al. 2011

Neurobiology of Aging

View full text Add to dashboard Cite

show abstract

“…The extent to which the EPP exceeds that necessary to initiate the action potential is usually called the safety factor for neuromuscular transmission. [2] The EPP is short-lived because the AChRs close spontaneously, ACh dissociates and escapes by diffusion or is hydrolysed by AChE. The calcium channels also close spontaneously.…”

Section: Review Article the Neuromuscular Junctionmentioning

confidence: 99%

Autoimmune disorders of the neuromuscular junction

Lang

Vincent

2009

Current Opinion in Pharmacology

View full text Add to dashboard Cite

The neuromuscular junction (NMJ) is a prototypic synapse although its structure is rather different from those of the central nervous system (CNS). The unmyelinated motor nerve terminals are separated from the postsynaptic membrane by a cleft that contains a basal lamina. This includes many proteins such as collagens, laminins, fibronectin and perlecan which help anchor some of the key elements involved in NMJ The neuromuscular junction (NMJ) is a specialized synapse with a complex structural and functional organization. It is a target for a variety of immunological disorders and these diseases usually respond well to immunotherapies. The understanding of the immunological basis of myasthenia gravis, the most common neuromuscular junction disorder, has improved in the recent years. Most patients have antibodies to the acetylcholine receptor (AChR), but around 10% have AChR antibodies that are only identified by novel methods, and up to 5% have muscle-speciÞ c kinase antibodies which deÞ ne a different subgroup of myasthenia. The spectrum of antibodies and their pathophysiological aspects are being elucidated. Even though less common, Lambert Eaton myasthenic syndrome (LEMS) is important to recognize. The abnormality in LEMS is a presynaptic failure to release enough packets of ACh, caused by antibodies to the presynaptic voltage-gated calcium channels. More than half these patients have a small cell carcinoma of lung. Acquired neuromyotonia (NMT) is a condition associated with muscle hyperactivity. Clinical features include muscle stiffness, cramps, myokymia, pseudomyotonia and weakness. The immune mechanisms of acquired NMT relate to loss of voltage-gated potassium channel function. This review will focus on the important recent developments in the immunemediated disorders of the NMJ.Key words: Gravis, Lambert Eaton myasthenic syndrome, neuromyotonia, neuromuscular junction, autoimmunity, acetylcholine receptor, voltage-gated channel development and function; for instance acetylcholine esterase (AChE) is localized via ColQ, a collagen-like molecule, to the basal lamina. Agrin and neuregulins, secreted from the nerve terminal, are bound by the basal lamina and interact with their receptors, playing an important role in the location of postsynaptic membrane proteins, voltage-gated calcium channels and the dystroglycans. The postsynaptic membrane at the NMJ forms a series of deep folds. The acetylcholine receptors (AChRs) are found at the top one-third of these folds, whereas the voltage-gated sodium channels are anchored at the bottom of the folds. The development of the NMJ is a fascinating area of research [1] and many of the proteins involved are relevant to disease ([ Figure 1] for a simple representation).The nerve action potential opens voltage-gated calcium channels (VGCCs) that are located in the motor nerve terminal [ Figure 1]. The resulting influx of calcium leads to the release of about 30 (in human muscle) individual packets of acetylcholine (ACh). Some of the ACh is hydrolysed by AChE but about 65%...

show abstract

“…This more pronounced rundown of ACh release at dKO NMJs is, however, not to be expected to negatively impact on successful synaptic transmission. From the mean dKO EPP amplitude of 24 mV and the published safety factor for the mouse NMJ of at least 2.4 (Wood and Slater, 2001) it can be calculated that EPPs of more than 10 mV will result in successful transmission. Even at maximal rundown (to a plateau level of ~66% of their initial value, at 70 Hz stimulation), dKO EPPs would remain ~16 mV, i.e.…”

Section: Increased Rundown Of High-rate Transmitter Release At Dko Symentioning

confidence: 99%