Safety Factor For Neuromuscular Transmission Research Articles

The Safety Factor for Neuromuscular Transmission: Effects of Dimethylsulphoxide, Cannabinoids and Synaptic Homeostasis.

BackgroundIn myasthenia gravis, impaired postsynaptic sensitivity to acetylcholine results in failure of neuromuscular transmission and fatiguing muscle weakness.ObjectiveDevelop an ex vivo muscle contraction assay to test cannabinoids and other substances that might act on the myasthenic neuromuscular junction to restore control of the muscle.MethodsTubocurarine was added to an ex vivo, mouse phrenic nerve-hemidiaphragm muscle preparation to reduce acetylcholine sensitivity. This produced a myasthenia-like decrement in twitch force during a train of 10 nerve impulses (3 / sec). Endplate potential (EPP) recordings were used to confirm and extend the findings.ResultsSurprisingly, addition to the bath of dimethylsulphoxide (DMSO), at concentrations as low as 0.1%(v/v), partially reversed the decrement in nerve-evoked force. Intracellular electrophysiology, conducted in the presence of tubocurarine, showed that DMSO increased the amplitudes of both the spontaneous miniature EPP (MEPP) and the (nerve-evoked) EPP. In the absence of tubocurarine (synaptic potentials at physiological levels), an adaptive fall in quantal content negated the DMSO-induced rise in EPP amplitude. The effects of cannabinoid receptor agonists (solubilized with DMSO) in the contraction assay do not support their further exploration as useful therapeutic agents for myasthenia gravis. CP 55,940 (a dual agonist for cannabinoid receptor types 1 and 2) reversed the beneficial effects of DMSO.Conclusions:We demonstrate a powerful effect of DMSO upon quantal amplitude that might mislead pharmacological studies of synaptic function wherever DMSO is used as a drug vehicle. Our results also show that compounds targeting impaired neuromuscular transmission should be tested under myasthenic-like conditions, so as to avoid confounding effects of synaptic homeostasis.

Cholesterol and the Safety Factor for Neuromuscular Transmission.

A present review is devoted to the analysis of literature data and results of own research. Skeletal muscle neuromuscular junction is specialized to trigger the striated muscle fiber contraction in response to motor neuron activity. The safety factor at the neuromuscular junction strongly depends on a variety of pre- and postsynaptic factors. The review focuses on the crucial role of membrane cholesterol to maintain a high efficiency of neuromuscular transmission. Cholesterol metabolism in the neuromuscular junction, its role in the synaptic vesicle cycle and neurotransmitter release, endplate electrogenesis, as well as contribution of cholesterol to the synaptogenesis, synaptic integrity, and motor disorders are discussed.

Neuromuscular synapse electrophysiology in myasthenia gravis animal models.

The neuromuscular junction (NMJ) forms the synaptic connection between a motor neuron and a skeletal muscle fiber. In order to achieve a sustained muscle contraction, this synapse has to reliably transmit motor neuronal action potentials onto the muscle fiber. To guarantee successful transmission even during intense activation of the NMJ, a safety factor of neuromuscular transmission exists. In the neuromuscular disorder myasthenia gravis (MG), autoantibodies are directed against acetylcholine receptors or, in the rarer variants, against other postsynaptic NMJ proteins. This causes loss of functional acetylcholine receptors, which compromises the safety factor of neuromuscular transmission, leading to the typical fatigable muscle weakness of MG. With intracellular microelectrode measurement of (miniature) endplate potentials at NMJs in ex vivo nerve-muscle preparations from MG animal models, these functional synaptic defects have been determined in much detail. Here, we describe the electrophysiological events at the normal NMJ and the pathoelectrophysiology at NMJs of animal models for MG.

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

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 invivo, 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.

Ryanodine and inositol triphosphate receptors modulate facilitation and tetanic depression at the frog neuromuscular junction.

Short-term plasticity of synaptic function is an important physiological control of transmitter release. Short-term plasticity can be regulated by intracellular calcium released by ryanodine and inositol triphosphate (IP3) receptors, but the role of these receptors at the neuromuscular junction is understood incompletely. We measured short-term plasticity of evoked endplate potential (EPP) amplitudes from frog neuromuscular junctions treated with ryanodine, 2-aminoethoxydiphenylborane (2-APB), or 1-[6-[[(17β)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U- 73122). Ryanodine decreases paired-pulse facilitation for intervals <20 ms and markedly decreases tetanic depression. Treatment with 2-APB reduces EPP amplitude, increases paired-pulse facilitation for intervals of <20 ms, and significantly reduces tetanic depression. U-73122 decreases EPP amplitude and decreases paired-pulse depression for intervals <20 ms. Ryanodine, IP3 receptors, and phospholipase C modulate short-term plasticity of transmitter release at the neuromuscular junction. These results suggest possible targets for improving the safety factor of neuromuscular transmission during repetitive activity of the neuromuscular junction.

Beneficial effect of crotamine in the treatment of myasthenic rats

Crotamine is a basic, low-molecular-weight peptide that, at low concentrations, improves neurotransmission in isolated neuromuscular preparations by modulating sodium channels. In this study, we compared the effects of crotamine and neostigmine on neuromuscular transmission in myasthenic rats. We used a conventional electromyographic technique in in-situ neuromuscular preparations and a 4-week treadmill program. During the in-situ electromyographic recording, neostigmine (17 μg/kg) caused short-term facilitation, whereas crotamine induced progressive and sustained twitch-tension enhancement during 140 min of recording (50 ± 5%, P < 0.05). On the treadmill evaluation, rats showed significant improvement in exercise tolerance, characterized by a decrease in the number of fatigue episodes after 2 weeks of a single-dose treatment with crotamine. These results indicate that crotamine is more efficient than neostigmine for enhancing muscular performance in myasthenic rats, possibly by improving the safety factor of neuromuscular transmission.

Safety Factor for Neuromuscular Transmission Is Reduced in Mild and Moderate Myasthenia Gravis Due to Loss of Both Sodium Channels and Acetylcholine Receptors (S35.006)

Objective: To evaluate the contributions of loss of Na + channels and acteylcholine receptors (AChR) to reduction in safety factor for neuromuscular transmission (SF) in patients with MGFA class IIa and IIIa myasthenia gravis (MG). I hypothesized that loss of endplate Na+ channels would contribute to the reduction of SF in patients with MG. Background Endplate Na + channels improve neuromuscular transmission by reducing the threshold depolarization needed to trigger an action potential (E AP ). In MG, AChRs and Na + channels are lost from the endplate. Na+ channels as well as AChRs were lost from the endplate membrane. Design/Methods: I used standard electrophysiological techniques to compare membrane currents and potentials in intercostal nerve-muscle preparations from 5 MGFA IIIa, 2 MGFA IIa and 7 control adult male subjects. Na + currents recorded using loose patch voltage clamp. Action potential (AP) characteristics measured with a 2 electrode clamp. Endplate potentials (EPPs) studied using μ-conotoxin GIIIb to block muscle Na + channels. The motor nerve was stimulated using a suction electrode. I report the findings for recordings from fast-glycolytic muscle fibers. Results: In MG, EPP was reduced from 40.2 ±1.3 to 30.1±1.3 mV (IIa) and 23.5 ±1.7 mV (IIIa) (p + channel loss increased E AP from −71.9 ±2.2 mV to -66.1 ±2.7 mV (IIa; p AP was the same for MG fibers and controls. The SF for neuromuscular transmission was reduced from 2.98 to 1.58 (IIa) and 1.09 (IIIa). Loss of Na + channels accounted for 53% (IIa) or 41% of the SF reduction. Reduction of EPP produced 47% (IIa) or 59% (IIIa) of the SF decrease. Conclusions: Loss of endplate Na + channels contributes to the reduced SF in MG to a similar extent as does the loss of endplate AChRs. Supported by: Department Veterans Affairs. Disclosure: Dr. Ruff has nothing to disclose.

Endplate contributions to the safety factor for neuromuscular transmission

The neuromuscular junction (NMJ), for most extremity and axial skeletal muscle fibers, with the exception of extraocular, middle ear, and some facial and pharyngeal muscles, is a 'slave' synapse that is designed to activate the muscle fiber every time the nerve terminal is activated. The fidelity of the NMJ hinges upon the electrical depolarization produced by activation of acetylcholine receptors (AChRs), called the endplate potential (EPP), being larger than is needed to trigger an action potential (AP) in the skeletal muscle fiber. The safety factor (SF) is a measure of how much larger the EPP is than the depolarization needed to trigger an AP (EAP). The SF depends on the amount of transmitter released, AChR density, EAP, and the effectiveness of the EPP in stimulating the Na(+) channels that trigger the AP. This study focuses on the postsynaptic factors that influence the SF and how the SF is altered in myasthenia gravis.

Extraneuronal toxicity of Alzheimer's β‐amyloid peptide: Comparative study on vertebrate skeletal muscles

Alzheimer's β-amyloid peptide (βAP) is known to possess a wide range of toxic effects on neurons in vitro and in vivo; however, there is little information available regarding its impact on other excitable tissues such as skeletal muscles, which, apart from brain cells, are thought to also be targets of βAP. Utilizing the combination of electrophysiology and myography, we investigated whether βAP also impairs the functioning of myocytes in frogs and mice. Although application of βAP in the range of 10(-6) to 10(-8) M induced depolarization of muscle fibers in both species, it impaired contractility in frogs but not in mice, by reducing endplate potential amplitude and increasing the threshold potential. Unchanged contractility in the mouse in the presence of βAP is due to a higher safety factor of neuromuscular transmission in mammals compared with amphibians. Possible clinical implications are discussed.

Endplate Na + Channels Loss Impairs Neuromuscular Transmission in Myasthenia Gravis

Myasthenia gravis (MG) is caused by acetylcholine receptor (AChR) antibodies inducing complement-medicated destruction of endplate membrane. Endplate Na+ channels enhance the safety factor for neuromuscular transmission by reducing the threshold depolarization needed to trigger an action potential (EAP). I previously demonstrated that MG antibodies do not directly alter the function of Na+ channels and that Na+ channels are lost by complement-mediated loss of endplate membrane. I examined the impact of postsynaptic voltage-gated Na+ channel loss on the SF. Comparing intercostal nerve-muscle preparations from controls and MG patients with moderate (M) or severe (S) MG, I found that endplate AChR loss decreased the endplate potential (EPP) from 40.2 ±1.3 to 30.1±1.3 mV (M) and 23.5 ±1.7 (S) (p < 0.001 for both). Endplate Na+ channel loss increased EAP from −71.9 ±2.2 to −66.1 ±2.7 (M; p < 0.01) and 62.3 ±2.7 mV (S; p < 0.001). In contrast, on extrajunctional membrane (> 0.1 cm from the endplate), EAP was the same for MG fibers and controls. The SF for neuromuscular transmission was reduced from 2.98 to 1.58 (M) and 1.09 (S). If the EPP was the same as control, the SF for MG fibers would have been 2.12 (M) or 1.86 (S). If EAP for MG fibers were the same as control fibers, the SF for MG fibers would have been 2.23 (M) or 1.74(S). In moderate MG, reduced EPP accounted for 47% of the SF reduction and increased EAP 53% of the SF reduction. In severe MG, reduced EPP accounted for 59% of the SF reduction and increased EAP 40% of the SF reduction. Conclusion: loss of endplate Na+ channels in MG contributes to the reduction in SF to a similar extent as does the loss of endplate AChRs.

How Myasthenia Gravis Alters the Safety Factor for Neuromuscular Transmission

Myasthenia gravis (MG), the best understood autoimmune disease, is characterized by antibodies directed against the skeletal muscle acetylcholine receptors (AChRs). An elevated concentration of Na+ channels at the endplate ensures the efficiency of neuromuscular transmission by reducing the threshold depolarization needed to trigger an action potential (EAP). Postsynaptic AChRs and voltage-gated Na+ channels are lost from the neuromuscular junction in MG. We studied the impact of postsynaptic voltage-gated Na+ channel loss on the safety factor for neuromuscular transmission (SF). Comparing intercostal nerve-muscle preparations from controls and MG patients, endplate AChR loss decreased the size of the endplate potential (EPP) from 40.2 ±1.3 mV to 23.5 ±1.7 mV (p < 0.001). Endplate Na+ channel loss in patients with MG increased EAP from −71.9 ±2.2 mV to 62.3 ±2.7 mV (p < 0.001). The SF was reduced from 2.98 to 1.09. If the EPP was the same as control, the SF for MG fibers would have been 1.86 rather than the observed value of 1.09. If EAP for MG fibers were the same as control fibers, the SF for MG fibers would have been 1.74. The reduction in EPP accounted for 59% of the reduction in SF and the increase in EAP produced 40% of the SF reduction. To evaluate whether AChR-specific antibody impaired the function of Na+ channels, we tested omohyoid nerve-muscle preparations from rats injected with monoclonal myasthenogenic IgG (passive transfer model of MG [PTMG]). AChR antibody that produced PTMG did not alter the function of Na+ channels. We conclude that loss of endplate Na+ channels in MG is due to complement-mediated loss of endplate membrane rather than a direct effect of myasthenogenic antibodies on Na+ channels. Loss of endplate Na+ channels caused 40% of the SF reduction in MG.

A relative weak leg muscle in the rolling Nagoya mouse as a model for Lambert–Eaton myasthenic syndrome

The Lambert–Eaton myasthenic syndrome (LEMS) is caused by auto-antibodies that affect the activity of presynaptic calcium channels at the neuromuscular junction. Weakness in LEMS is particularly affecting the legs. Here we used leg muscles from the rolling Nagoya (RN) mouse with a R1262G mutation in the alpha-1 subunit of the P/Q-type (Ca v2.1) calcium channel. We found that in homozygote flexor digitorum brevis (FDB) muscles the contractions by single pulses, expressed as relative to contractions by direct stimulation, were smaller (43%) than in controls (94%) with 0.5 mM Ca 2+ in the medium. In both homozygote RN and control animals the contractions of the FDB by single pulses were affected more than the corresponding contractions of the diaphragm; RN muscles with 0.5 mM Ca 2+, FDB 42% and Dia 91%, respectively; control muscles with 0.25 mM Ca 2+, FDB 9% and Dia 39%, respectively. At 40 Hz stimulation this difference was 35% and 76% with 0.35 mM Ca 2+. In RN and control mice both muscles were about equally sensitive to 200 and 400 µM tubocurarine. The results suggest that leg weakness in LEMS may result from a relatively small safety factor of neuromuscular transmission and that this could become particularly prominent when the activity of calcium channels is diminished.

How myasthenia gravis alters the safety factor for neuromuscular transmission

Myasthenia gravis (MG), the most common of autoimmune myasthenic syndromes, is characterized by antibodies directed against the skeletal muscle acetylcholine receptors (AChRs). Endplate Na + channels ensure the efficiency of neuromuscular transmission by reducing the threshold depolarization needed to trigger an action potential. Postsynaptic AChRs and voltage-gated Na + channels are both lost from the neuromuscular junction in MG. This study examined the impact of postsynaptic voltage-gated Na + channel loss on the safety factor for neuromuscular transmission. In intercostal nerve–muscle preparations from MG patients, we found that endplate AChR loss decreases the size of the endplate potential, and endplate Na + channel loss increases the threshold depolarization needed to produce a muscle action potential. To evaluate whether AChR-specific antibody impairs the function of Na + channels, we tested omohyoid nerve–muscle preparations from rats injected with monoclonal myasthenogenic IgG (passive transfer model of MG [PTMG]). The AChR antibody that produces PTMG did not alter the function of Na + channels. We conclude that loss of endplate Na + channels in MG is due to complement-mediated loss of endplate membrane rather than a direct effect of myasthenogenic antibodies on endplate Na + channels.

Severely impaired neuromuscular synaptic transmission causes muscle weakness in the Cacna1a‐mutant mouse rolling Nagoya

The ataxic mouse rolling Nagoya (RN) carries a missense mutation in the Cacna1a gene, encoding the pore-forming subunit of neuronal Ca(v)2.1 (P/Q-type) Ca2+ channels. Besides being the predominant type of Ca(v) channel in the cerebellum, Ca(v)2.1 channels mediate acetylcholine (ACh) release at the peripheral neuromuscular junction (NMJ). Therefore, Ca(v)2.1 dysfunction induced by the RN mutation may disturb ACh release at the NMJ. The dysfunction may resemble the situation in Lambert-Eaton myasthenic syndrome (LEMS), in which autoantibodies target Ca(v)2.1 channels at NMJs, inducing severely reduced ACh release and resulting in muscle weakness. We tested neuromuscular function of RN mice and characterized transmitter release properties at their NMJs in diaphragm, soleus and flexor digitorum brevis muscles. Clinical muscle weakness and fatigue were demonstrated using repetitive nerve-stimulation electromyography, grip strength testing and an inverted grid hanging test. Muscle contraction experiments showed a compromised safety factor of neuromuscular transmission. In ex vivo electrophysiological experiments we found severely impaired ACh release. Compared to wild-type, RN NMJs had 50-75% lower nerve stimulation-evoked transmitter release, explaining the observed muscle weakness. Surprisingly, the reduction in evoked release was accompanied by an approximately 3-fold increase in spontaneous ACh release. This synaptic phenotype suggests a complex effect of the RN mutation on different functional Ca(v)2.1 channel parameters, presumably with a positive shift in activation potential as a prevailing feature. Taken together, our studies indicate that the gait abnormality of RN mice is due to a combination of ataxia and muscle weakness and that RN models aspects of the NMJ dysfunction in LEMS.

Safety factor for neuromuscular transmission at type‐identified diaphragm fibers

The safety factor (SF) for neuromuscular transmission varies across limb muscles of different fiber-type composition. Using intracellular recordings in rat diaphragm fibers, we found that SF varies across muscle fiber types (even within a single muscle), being larger for type IIx or IIb fibers than for type I or IIa fibers. Fiber-type differences in activation history or mechanical load may contribute to differences in SF and are important determinants of neuromuscular plasticity.

Enhanced neuromuscular transmission efficacy in overloaded rat plantaris muscle.

To better understand the effect of muscle hypertrophy on the physiological properties of transmitter release, we investigated neuromuscular transmission (NMT) efficacy in overloaded rat plantaris muscle in situ. In the overload group, following bilateral tenotomy of plantaris synergists, rats were confined to wheel-cages. Age-matched rats in the control group were confined to plastic cages. During the terminal experiment, muscle action potentials were blocked using micro-conotoxin, and full-sized endplate potentials (EPPs) were recorded at 25, 50, and 75 HZ to determine their amplitude rundown. Quantal contents for the control and overload groups were 37.0 and 74.3, respectively (P <0.01). There was a significant group difference in EPP amplitude rundown at all frequencies examined, with increased rundown occurring in the overload group (P < 0.01). Cumulative quantal release was 139% and 153% higher in the overload group at 25 and 50 HZ, respectively (P < 0.05). Together, these data suggest the safety factor for NMT is increased by neuromuscular overload. Furthermore, these findings support and supplement previously reported activity-dependent improvements in NMT efficacy that are probably mediated via presynaptic adaptations.

Neurophysiology of the Neuromuscular Junction: Overview

Abstract: This manuscript reviews the physiology of neuromuscular transmission with emphasis on four features: (1) the structure of the neuromuscular junction, (2) release of vesicles of acetylcholine from the nerve terminal, (3) the roles of postsynaptic Na+ channels and acetylcholine receptors in converting the chemical signal from the nerve terminal into a propagated action potential on the muscle fiber, and (4) the safety factor for neuromuscular transmission. It also introduces new information about how the neuromuscular junction maintains physiological integrity during muscle fiber stretch and contraction.

Blockade of neuronal facilitatory nicotinic receptors containing alpha 3 beta 2 subunits contribute to tetanic fade in the rat isolated diaphragm.

Nicotinic receptor (nAChR) subtypes involved in pre- and postjunctional actions underlying tetanic fade were studied in rat phrenic-nerve hemidiaphragms. We investigated the ability of subtype-specific nAChR antagonists to depress nerve-evoked contractions and [(3)H]-acetylcholine ([(3)H]-ACh) release. Muscle tension was transiently increased during brief high frequency trains (50 Hz for 5 sec). The rank potency order of nAChR antagonists to reduce tetanic peak tension was alpha-bungarotoxin > d-tubocurarine >> mecamylamine > hexamethonium. Reduction of maximal tetanic tension produced by dihydro-beta-erythroidine (0.03-10 microM), methyllycaconitine (0.003-3 microM), and alpha-conotoxin MII (0.001-0.3 microM) did not exceed 30%. Besides reduction of peak tension d-tubocurarine (0.1-0.7 microM), mecamylamine (0.1-300 microM), and hexamethonium (30-3,000 microM) also caused tetanic fading. With alpha-conotoxin MII (0.001-0.3 microM) and dihydro-beta-erythroidine (0.03-10 microM), tetanic fade was evident only after decreasing the safety factor of neuromuscular transmission (with high magnesium ions, 6-7 mM). The antagonist rank potency order to reduce evoked (50 Hz for 5 sec) [(3)H]-ACh release from motor nerve terminals was alpha-conotoxin MII (0.1 microM) > dihydro-beta-erythroidine (1 microM) approximately d-tubocurarine (1 microM) > mecamylamine (100 microM) > hexamethonium (1,000 microM). When applied in a concentration (0.3 microM) above that producing tetanic paralysis, alpha-bungarotoxin failed to affect [(3)H]-ACh release. Data obtained suggest that postjunctional neuromuscular relaxants interact with alpha-bungarotoxin-sensitive nicotinic receptors containing alpha1-subunits, whereas blockade of neuronal alpha3beta2-containing receptors produce tetanic fade by breaking nicotinic autofacilitation of acetylcholine release.

Safety margin at single neuromuscular junctions.

Jitter measurement with axonal microstimulation was used to study synaptic function at 115 neuromuscular junctions (NMJs) of normal subjects at various stimulation rates. Jitter was lowest at 0.5 Hz; it increased slightly at 1, 2, and 5 Hz and remained at that level at 10 Hz (a light work load) and 20 Hz (a heavy work load); and it increased further at 50 Hz (an extreme load). This pattern was seen for the majority of the NMJs, suggesting a high safety factor of neuromuscular transmission maintained rather uniformly over a wide range of discharge rates. A proportion of the normal NMJs had relatively large jitter; these tended to show prominent facilitation as the rate was raised from 5 or 10 to 20 Hz. Similar but more dramatic facilitation improving the safety factor was seen at most NMJs in myasthenia, which was studied for comparison. Such facilitation was not found at normal NMJs with low jitter.

Computer simulation of jitter phenomenon in neuromuscular transmission disorders.

Neuromuscular jitter is a sensitive measure of the safety factor of neuromuscular transmission. Nevertheless, the actual relationship between jitter and the safety factor is unknown because these parameters have not been simultaneously measured. In order to explore the theoretical relationship between them, a computer model of mammalian neuromuscular transmission has been developed. If the safety factor is expressed as the absolute value of the natural logarithm of the probability of a block, the model predicts a double exponential relationship between the safety factor and jitter, except when the percentage of blocks is greater than 90%. In that case, the jitter value decreases. Simulation of acetylcholinesterase inhibition shows that this treatment decreases the neuromuscular transmission blocks more effectively in postsynaptic than in presynaptic disorders. In contrast, when the percentage of blocks is greater than 60%, the jitter value increases in both conditions.