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J Palace - One of the best experts on this subject based on the ideXlab platform.
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congenital myasthenic syndrome due to a tor1aip1 mutation a new disease pathway for impaired synaptic transmission
Brain communications, 2020Co-Authors: Judith Cossins, Richard Webster, Susan Maxwell, Pedro Rodriguez M Cruz, J Palace, Ravi Knight, John Gareth Llewelyn, Jiyeon Shin, David BeesonAbstract:Congenital myasthenic syndromes are inherited disorders characterized by fatiguable muscle weakness resulting from impaired signal transmission at the neuromuscular junction. Causative mutations have been identified in genes that can affect the synaptic function or structure. We identified a homozygous frameshift deletion c.127delC, p. Pro43fs in TOR1AIP1 in two siblings with limb-girdle weakness and impaired transmission at the neuromuscular synapse. TOR1AIP1 encodes the inner nuclear membrane protein lamin-associated protein 1. On muscle biopsy from the index case, lamin-associated protein 1 was absent from myonuclei. A mouse model with lamin-associated protein 1 conditionally knocked out in striated muscle was used to analyse the role of lamin-associated protein 1 in synaptic dysfunction. Model mice develop fatiguable muscle weakness as demonstrated by using an inverted screen hang test. Electromyography on the mice revealed a decrement on repetitive nerve stimulation. Ex vivo analysis of hemi-diaphragm preparations showed both miniature and evoked End-Plate Potential half-widths were prolonged which was associated with upregulation of the foetal acetylcholine receptor γ subunit. Neuromuscular junctions on extensor digitorum longus muscles were enlarged and fragmented, and the number of subsynaptic nuclei was significantly increased. Following these findings, electromyography was performed on cases of other nuclear envelopathies caused by mutations in LaminA/C or emerin, but decrement on repetitive nerve stimulation or other indications of defective neuromuscular transmission were not seen. Thus, this report highlights the first nuclear membrane protein in which defective function can lead to impaired synaptic transmission.
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β2 adrenergic receptor agonists ameliorate the adverse effect of long term pyridostigmine on neuromuscular junction structure
Brain, 2019Co-Authors: An Vanhaesebrouck, Richard Webster, Susan Maxwell, Pedro Rodriguez M Cruz, Judith Cossins, James Wickens, Hakan Cetin, J Cheung, Hayley Ramjattan, J PalaceAbstract:Acetylcholine receptor deficiency is the most common form of the congenital myasthenic syndromes, a heterogeneous collection of genetic disorders of neuromuscular transmission characterized by fatiguable muscle weakness. Most patients with acetylcholine receptor deficiency respond well to acetylcholinesterase inhibitors; however, in some cases the efficacy of acetylcholinesterase inhibitors diminishes over time. Patients with acetylcholine receptor deficiency can also benefit from the addition of a β2-adrenergic receptor agonist to their medication. The working mechanism of β2-adrenergic agonists in myasthenic patients is not fully understood. Here, we report the long-term follow-up for the addition of β2-adrenergic agonists for a cohort of patients with acetylcholine receptor deficiency on anticholinesterase medication that demonstrates a sustained quantitative improvement. Coincidently we used a disease model to mirror the treatment of acetylcholine receptor deficiency, and demonstrate improved muscle fatigue, improved neuromuscular transmission and improved synaptic structure resulting from the addition of the β2-adrenergic agonist salbutamol to the anticholinesterase medication pyridostigmine. Following an initial improvement in muscle fatiguability, a gradual decline in the effect of pyridostigmine was observed in mice treated with pyridostigmine alone (P < 0.001). Combination therapy with pyridostigmine and salbutamol counteracted this decline (P < 0.001). Studies of compound muscle action Potential decrement at high nerve stimulation frequencies (P < 0.05) and miniature End-Plate Potential amplitude analysis (P < 0.01) showed an improvement in mice following combination therapy, compared to pyridostigmine monotherapy. Pyridostigmine alone reduced postsynaptic areas (P < 0.001) and postsynaptic folding (P < 0.01). Combination therapy increased postsynaptic area (P < 0.001) and promoted the formation of postsynaptic junctional folds (P < 0.001), in particular in fast-twitch muscles. In conclusion, we demonstrate for the first time how the improvement seen in patients from adding salbutamol to their medication can be explained in an experimental model of acetylcholine receptor deficiency, the most common form of congenital myasthenic syndrome. Salbutamol enhances neuromuscular junction synaptic structure by counteracting the detrimental effects of long-term acetylcholinesterase inhibitors on the postsynaptic neuromuscular junction. The results have implications for both autoimmune and genetic myasthenias where anticholinesterase medication is a standard treatment.
Richard Webster - One of the best experts on this subject based on the ideXlab platform.
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congenital myasthenic syndrome due to a tor1aip1 mutation a new disease pathway for impaired synaptic transmission
Brain communications, 2020Co-Authors: Judith Cossins, Richard Webster, Susan Maxwell, Pedro Rodriguez M Cruz, J Palace, Ravi Knight, John Gareth Llewelyn, Jiyeon Shin, David BeesonAbstract:Congenital myasthenic syndromes are inherited disorders characterized by fatiguable muscle weakness resulting from impaired signal transmission at the neuromuscular junction. Causative mutations have been identified in genes that can affect the synaptic function or structure. We identified a homozygous frameshift deletion c.127delC, p. Pro43fs in TOR1AIP1 in two siblings with limb-girdle weakness and impaired transmission at the neuromuscular synapse. TOR1AIP1 encodes the inner nuclear membrane protein lamin-associated protein 1. On muscle biopsy from the index case, lamin-associated protein 1 was absent from myonuclei. A mouse model with lamin-associated protein 1 conditionally knocked out in striated muscle was used to analyse the role of lamin-associated protein 1 in synaptic dysfunction. Model mice develop fatiguable muscle weakness as demonstrated by using an inverted screen hang test. Electromyography on the mice revealed a decrement on repetitive nerve stimulation. Ex vivo analysis of hemi-diaphragm preparations showed both miniature and evoked End-Plate Potential half-widths were prolonged which was associated with upregulation of the foetal acetylcholine receptor γ subunit. Neuromuscular junctions on extensor digitorum longus muscles were enlarged and fragmented, and the number of subsynaptic nuclei was significantly increased. Following these findings, electromyography was performed on cases of other nuclear envelopathies caused by mutations in LaminA/C or emerin, but decrement on repetitive nerve stimulation or other indications of defective neuromuscular transmission were not seen. Thus, this report highlights the first nuclear membrane protein in which defective function can lead to impaired synaptic transmission.
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β2 adrenergic receptor agonists ameliorate the adverse effect of long term pyridostigmine on neuromuscular junction structure
Brain, 2019Co-Authors: An Vanhaesebrouck, Richard Webster, Susan Maxwell, Pedro Rodriguez M Cruz, Judith Cossins, James Wickens, Hakan Cetin, J Cheung, Hayley Ramjattan, J PalaceAbstract:Acetylcholine receptor deficiency is the most common form of the congenital myasthenic syndromes, a heterogeneous collection of genetic disorders of neuromuscular transmission characterized by fatiguable muscle weakness. Most patients with acetylcholine receptor deficiency respond well to acetylcholinesterase inhibitors; however, in some cases the efficacy of acetylcholinesterase inhibitors diminishes over time. Patients with acetylcholine receptor deficiency can also benefit from the addition of a β2-adrenergic receptor agonist to their medication. The working mechanism of β2-adrenergic agonists in myasthenic patients is not fully understood. Here, we report the long-term follow-up for the addition of β2-adrenergic agonists for a cohort of patients with acetylcholine receptor deficiency on anticholinesterase medication that demonstrates a sustained quantitative improvement. Coincidently we used a disease model to mirror the treatment of acetylcholine receptor deficiency, and demonstrate improved muscle fatigue, improved neuromuscular transmission and improved synaptic structure resulting from the addition of the β2-adrenergic agonist salbutamol to the anticholinesterase medication pyridostigmine. Following an initial improvement in muscle fatiguability, a gradual decline in the effect of pyridostigmine was observed in mice treated with pyridostigmine alone (P < 0.001). Combination therapy with pyridostigmine and salbutamol counteracted this decline (P < 0.001). Studies of compound muscle action Potential decrement at high nerve stimulation frequencies (P < 0.05) and miniature End-Plate Potential amplitude analysis (P < 0.01) showed an improvement in mice following combination therapy, compared to pyridostigmine monotherapy. Pyridostigmine alone reduced postsynaptic areas (P < 0.001) and postsynaptic folding (P < 0.01). Combination therapy increased postsynaptic area (P < 0.001) and promoted the formation of postsynaptic junctional folds (P < 0.001), in particular in fast-twitch muscles. In conclusion, we demonstrate for the first time how the improvement seen in patients from adding salbutamol to their medication can be explained in an experimental model of acetylcholine receptor deficiency, the most common form of congenital myasthenic syndrome. Salbutamol enhances neuromuscular junction synaptic structure by counteracting the detrimental effects of long-term acetylcholinesterase inhibitors on the postsynaptic neuromuscular junction. The results have implications for both autoimmune and genetic myasthenias where anticholinesterase medication is a standard treatment.
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presence and pathogenic relevance of antibodies to clustered acetylcholine receptor in ocular and generalized myasthenia gravis
JAMA Neurology, 2012Co-Authors: Saiju Jacob, Richard Webster, S Viegas, M I Leite, J Cossins, R Kennett, David Hiltonjones, B P Morgan, Angela VincentAbstract:Background Clustered acetylcholine receptor antibodies (clustered AChR-Abs) have been detected in a proportion of patients with previously “seronegative” (SN) generalized myasthenia gravis (GMG), but their presence in patients with ocular MG (OMG) and their pathogenicity in vivo are unknown. Objective To test the presence of clustered AChR-Abs and their pathophysiologic properties in patients with SNMG. Design Screening and diagnostic tests. Setting Regional specialist myasthenia center and clinical laboratory. Patients Serum samples from 16 patients with SN and OMG were tested for binding to clustered AChRs. Results from 28 further SN patients (14 OMG) were correlated with their single fiber electromyography values. Main Outcome Measures Presence, complement-fixation capacity, correlation with neurophysiologic changes, and in vivo pathogenicity of clustered AChR-Abs. Results Up to 50% of patients with previous SN-OMG had complement-fixing IgG1 clustered AChR-Abs. IgG binding (n = 28) and complement deposition (n = 21) each correlated with the mean consecutive difference (jitter) on single-fiber electromyography. Injection of purified IgG from 2 patients with clustered AChR-Abs into wild-type or complement regulator–deficient mice reduced miniature end plate Potential amplitudes to an extent similar to that found with AChR-Abs, and complement was deposited at the end plates. A trend was noted toward an increase in the number of packets of acetylcholine released (quantal content). Conclusions A proportion of patients with SN-GMG or OMG have clustered AChR-Abs that correlate with their electrophysiologic features. Clustered AChR-Abs can passively transfer disease to mice, demonstrating their pathogenicity, and the mechanisms seem similar to those of patients with typical AChR-Abs.
An Vanhaesebrouck - One of the best experts on this subject based on the ideXlab platform.
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β2 adrenergic receptor agonists ameliorate the adverse effect of long term pyridostigmine on neuromuscular junction structure
Brain, 2019Co-Authors: An Vanhaesebrouck, Richard Webster, Susan Maxwell, Pedro Rodriguez M Cruz, Judith Cossins, James Wickens, Hakan Cetin, J Cheung, Hayley Ramjattan, J PalaceAbstract:Acetylcholine receptor deficiency is the most common form of the congenital myasthenic syndromes, a heterogeneous collection of genetic disorders of neuromuscular transmission characterized by fatiguable muscle weakness. Most patients with acetylcholine receptor deficiency respond well to acetylcholinesterase inhibitors; however, in some cases the efficacy of acetylcholinesterase inhibitors diminishes over time. Patients with acetylcholine receptor deficiency can also benefit from the addition of a β2-adrenergic receptor agonist to their medication. The working mechanism of β2-adrenergic agonists in myasthenic patients is not fully understood. Here, we report the long-term follow-up for the addition of β2-adrenergic agonists for a cohort of patients with acetylcholine receptor deficiency on anticholinesterase medication that demonstrates a sustained quantitative improvement. Coincidently we used a disease model to mirror the treatment of acetylcholine receptor deficiency, and demonstrate improved muscle fatigue, improved neuromuscular transmission and improved synaptic structure resulting from the addition of the β2-adrenergic agonist salbutamol to the anticholinesterase medication pyridostigmine. Following an initial improvement in muscle fatiguability, a gradual decline in the effect of pyridostigmine was observed in mice treated with pyridostigmine alone (P < 0.001). Combination therapy with pyridostigmine and salbutamol counteracted this decline (P < 0.001). Studies of compound muscle action Potential decrement at high nerve stimulation frequencies (P < 0.05) and miniature End-Plate Potential amplitude analysis (P < 0.01) showed an improvement in mice following combination therapy, compared to pyridostigmine monotherapy. Pyridostigmine alone reduced postsynaptic areas (P < 0.001) and postsynaptic folding (P < 0.01). Combination therapy increased postsynaptic area (P < 0.001) and promoted the formation of postsynaptic junctional folds (P < 0.001), in particular in fast-twitch muscles. In conclusion, we demonstrate for the first time how the improvement seen in patients from adding salbutamol to their medication can be explained in an experimental model of acetylcholine receptor deficiency, the most common form of congenital myasthenic syndrome. Salbutamol enhances neuromuscular junction synaptic structure by counteracting the detrimental effects of long-term acetylcholinesterase inhibitors on the postsynaptic neuromuscular junction. The results have implications for both autoimmune and genetic myasthenias where anticholinesterase medication is a standard treatment.
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β2-Adrenergic receptor agonists ameliorate the adverse effect of long-term pyridostigmine on neuromuscular junction structure.
'Organisation for Economic Co-Operation and Development (OECD)', 2019Co-Authors: An Vanhaesebrouck, Webster Richard, Maxwell Susan, Rodriguez Cruz, Pedro M, Cossins Judith, Wickens James, Liu Wei-wei, Cetin Hakan, Cheung Jonathan, Ramjattan HayleyAbstract:Acetylcholine receptor deficiency is the most common form of the congenital myasthenic syndromes, a heterogeneous collection of genetic disorders of neuromuscular transmission characterized by fatiguable muscle weakness. Most patients with acetylcholine receptor deficiency respond well to acetylcholinesterase inhibitors; however, in some cases the efficacy of acetylcholinesterase inhibitors diminishes over time. Patients with acetylcholine receptor deficiency can also benefit from the addition of a β2-adrenergic receptor agonist to their medication. The working mechanism of β2-adrenergic agonists in myasthenic patients is not fully understood. Here, we report the long-term follow-up for the addition of β2-adrenergic agonists for a cohort of patients with acetylcholine receptor deficiency on anticholinesterase medication that demonstrates a sustained quantitative improvement. Coincidently we used a disease model to mirror the treatment of acetylcholine receptor deficiency, and demonstrate improved muscle fatigue, improved neuromuscular transmission and improved synaptic structure resulting from the addition of the β2-adrenergic agonist salbutamol to the anticholinesterase medication pyridostigmine. Following an initial improvement in muscle fatiguability, a gradual decline in the effect of pyridostigmine was observed in mice treated with pyridostigmine alone (P < 0.001). Combination therapy with pyridostigmine and salbutamol counteracted this decline (P < 0.001). Studies of compound muscle action Potential decrement at high nerve stimulation frequencies (P < 0.05) and miniature End-Plate Potential amplitude analysis (P < 0.01) showed an improvement in mice following combination therapy, compared to pyridostigmine monotherapy. Pyridostigmine alone reduced postsynaptic areas (P < 0.001) and postsynaptic folding (P < 0.01). Combination therapy increased postsynaptic area (P < 0.001) and promoted the formation of postsynaptic junctional folds (P < 0.001), in particular in fast-twitch muscles. In conclusion, we demonstrate for the first time how the improvement seen in patients from adding salbutamol to their medication can be explained in an experimental model of acetylcholine receptor deficiency, the most common form of congenital myasthenic syndrome. Salbutamol enhances neuromuscular junction synaptic structure by counteracting the detrimental effects of long-term acetylcholinesterase inhibitors on the postsynaptic neuromuscular junction. The results have implications for both autoimmune and genetic myasthenias where anticholinesterase medication is a standard treatment.This work was mainly funded through a Wellcome trust clinical research training fellowship to A.V. 103406/Z/13/Z. Additional funding was obtained from MRC programme grant MR/M006824 (D.B)
John G Nicholls - One of the best experts on this subject based on the ideXlab platform.
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how acetylcholine gives rise to current at the motor end plate
The Journal of Physiology, 2007Co-Authors: John G NichollsAbstract:At about the same time as Hodgkin and Huxley's work on squid axons appeared in The Journal of Physiology, Paul Fatt and Bernard Katz published ‘An analysis of the End-Plate Potential recorded with an intracellular electrode’ (Fatt & Katz, 1951). This was a revolutionary paper that for the first time explained how a chemical transmitter reacted with its receptors to give rise to an electrical signal. Fatt and Katz provided definitive answers to a host of questions regarding acetylcholine-induced permeability changes (questions that experts in the field had not even thought of). Thereafter, it became possible to study transmitters other than acetylcholine, and to analyse transmission in the central nervous system. What was known about the End-Plate Potential at that time? Here are some quotes from Fulton's widely read ‘Textbook of Physiology’ (1949): ‘How the nerve impulse produces the End-Plate Potential has not been settled …’ ‘The electrical theory holds that currents from … nerve terminals are adequate to set up the End-Plate Potential …’ ‘The chemical theory holds that the transmitter is acetylcholine …’ ‘Nachmansohn … proposes that acetylcholine is liberated in the (muscle) End-Plate by…current from the nerve ending.’ (Italics in original.) It would have been an unfair exam question, when I took the BSc Special in Physiology in 1951 (before starting my PhD with Katz), to ask: ‘Explain how activated acetylcholine receptors produce a depolarization at the End-Plate’. The discoveries in Fatt & Katz's 1951 paper are so abundant and original that it is hard to do them justice. Here I summarize the principal results. First, intracellular recordings showed that acetylcholine sets up a localized graded Potential at the frog muscle motor End-Plate; this declines and becomes slowed over distance, in quantitatively the same manner as ‘electrotonic’ Potentials produced by injecting current. Second, from values that had been derived for membrane resistance and capacitance, Fatt and Katz estimated the current produced at the End-Plate by transmitter. This current was briefer than the voltage change, the time course of which depended on the time constant of the membrane. Moreover, the amplitude of the synaptic current was far too great (approximately 10−12 mol of univalent ions per impulse), to be explained by current spread from tiny nerve terminals or from entry into the End-Plate of acetylcholine released by the nerve (a possibility suggested by Fatt in, 1950). Observations that might have appeared trivial explained the mechanism of acetylcholine action: the action Potential recorded at the End-Plate had a smaller overshoot when it arose from the action of acetylcholine than after direct electrical stimulation of the muscle. This suggested that acetylcholine punched a hole, a leak resistance of about 20 000 Ω, in the End-Plate membrane. This leak allowed ions to flow passively along their electrochemical gradients into or out of the muscle fibre. The receptor mechanism was not sensitive to depolarization. At that time it was not possible to do voltage clamp experiments on muscle: accordingly (so ingenious this!) to test the effect of membrane Potential on synaptic currents, the muscle was stimulated electrically to produce an action Potential. This swept from one end of the muscle fibre to the other past the End-Plate. At the same time the nerve was stimulated to release transmitter at different phases of the action Potential. At the peak of the action Potential, acetylcholine gave rise to an outward instead of an inward current; at a Potential of about −15 mV (during the falling phase), acetylcholine produced no additional current. Some words about techniques. Today, these experiments would pose few technical problems. But the cathode followers and DC amplifiers available at the time depended on large car batteries and needed constant balancing, the oscilloscope camera was a horror, microelectrodes were pulled by hand the night before, and analysis had to be done by measurements made from projected film. And it is still hard to record reliably from contracting muscles. The principal conclusions were, first, that the transmitter acts on receptors located at the motor End-Plate to open voltage-insensitive channels (not a word that could be used at that time); the increased permeability allowed both sodium and potassium to flow. (In these experiments they could not rule out participation by anions.) As a result, there occurred enormous amplification at the synapse. The voltage change depended on the membrane Potential and on the resistance (i.e. diameter) of the muscle fibre. These experiments created foundations upon which one could formulate new, testable concepts about excitation and inhibition in the central nervous system. Depending on the ion species to which the transmitter made the postsynaptic membrane more permeable, the synaptic signal could drive the Potential toward or away from threshold. Indeed, Fatt with Coombs and Eccles (Coombs et al. 1955) later demonstrated anion permeability changes induced by inhibitory transmitters (of unknown identity) in the spinal cord, and by the time their 1951 paper appeared, Fatt and Katz (1951) had already made key observations that led to the discovery of quantal release. The harmonious partnership of these two marvellous scientists showed how skilful and imaginative experiments can produce completely new approaches to important problems, provided that speculations are constrained by rigorous quantitative measurements. After the appearance of this paper, the study of synaptic transmission became transformed. It is hard for me to define what constitutes ‘beauty’ in science. If I had to point to just one paper to show what I mean, it would be Fatt & Katz (1951).
Susan Maxwell - One of the best experts on this subject based on the ideXlab platform.
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congenital myasthenic syndrome due to a tor1aip1 mutation a new disease pathway for impaired synaptic transmission
Brain communications, 2020Co-Authors: Judith Cossins, Richard Webster, Susan Maxwell, Pedro Rodriguez M Cruz, J Palace, Ravi Knight, John Gareth Llewelyn, Jiyeon Shin, David BeesonAbstract:Congenital myasthenic syndromes are inherited disorders characterized by fatiguable muscle weakness resulting from impaired signal transmission at the neuromuscular junction. Causative mutations have been identified in genes that can affect the synaptic function or structure. We identified a homozygous frameshift deletion c.127delC, p. Pro43fs in TOR1AIP1 in two siblings with limb-girdle weakness and impaired transmission at the neuromuscular synapse. TOR1AIP1 encodes the inner nuclear membrane protein lamin-associated protein 1. On muscle biopsy from the index case, lamin-associated protein 1 was absent from myonuclei. A mouse model with lamin-associated protein 1 conditionally knocked out in striated muscle was used to analyse the role of lamin-associated protein 1 in synaptic dysfunction. Model mice develop fatiguable muscle weakness as demonstrated by using an inverted screen hang test. Electromyography on the mice revealed a decrement on repetitive nerve stimulation. Ex vivo analysis of hemi-diaphragm preparations showed both miniature and evoked End-Plate Potential half-widths were prolonged which was associated with upregulation of the foetal acetylcholine receptor γ subunit. Neuromuscular junctions on extensor digitorum longus muscles were enlarged and fragmented, and the number of subsynaptic nuclei was significantly increased. Following these findings, electromyography was performed on cases of other nuclear envelopathies caused by mutations in LaminA/C or emerin, but decrement on repetitive nerve stimulation or other indications of defective neuromuscular transmission were not seen. Thus, this report highlights the first nuclear membrane protein in which defective function can lead to impaired synaptic transmission.
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β2 adrenergic receptor agonists ameliorate the adverse effect of long term pyridostigmine on neuromuscular junction structure
Brain, 2019Co-Authors: An Vanhaesebrouck, Richard Webster, Susan Maxwell, Pedro Rodriguez M Cruz, Judith Cossins, James Wickens, Hakan Cetin, J Cheung, Hayley Ramjattan, J PalaceAbstract:Acetylcholine receptor deficiency is the most common form of the congenital myasthenic syndromes, a heterogeneous collection of genetic disorders of neuromuscular transmission characterized by fatiguable muscle weakness. Most patients with acetylcholine receptor deficiency respond well to acetylcholinesterase inhibitors; however, in some cases the efficacy of acetylcholinesterase inhibitors diminishes over time. Patients with acetylcholine receptor deficiency can also benefit from the addition of a β2-adrenergic receptor agonist to their medication. The working mechanism of β2-adrenergic agonists in myasthenic patients is not fully understood. Here, we report the long-term follow-up for the addition of β2-adrenergic agonists for a cohort of patients with acetylcholine receptor deficiency on anticholinesterase medication that demonstrates a sustained quantitative improvement. Coincidently we used a disease model to mirror the treatment of acetylcholine receptor deficiency, and demonstrate improved muscle fatigue, improved neuromuscular transmission and improved synaptic structure resulting from the addition of the β2-adrenergic agonist salbutamol to the anticholinesterase medication pyridostigmine. Following an initial improvement in muscle fatiguability, a gradual decline in the effect of pyridostigmine was observed in mice treated with pyridostigmine alone (P < 0.001). Combination therapy with pyridostigmine and salbutamol counteracted this decline (P < 0.001). Studies of compound muscle action Potential decrement at high nerve stimulation frequencies (P < 0.05) and miniature End-Plate Potential amplitude analysis (P < 0.01) showed an improvement in mice following combination therapy, compared to pyridostigmine monotherapy. Pyridostigmine alone reduced postsynaptic areas (P < 0.001) and postsynaptic folding (P < 0.01). Combination therapy increased postsynaptic area (P < 0.001) and promoted the formation of postsynaptic junctional folds (P < 0.001), in particular in fast-twitch muscles. In conclusion, we demonstrate for the first time how the improvement seen in patients from adding salbutamol to their medication can be explained in an experimental model of acetylcholine receptor deficiency, the most common form of congenital myasthenic syndrome. Salbutamol enhances neuromuscular junction synaptic structure by counteracting the detrimental effects of long-term acetylcholinesterase inhibitors on the postsynaptic neuromuscular junction. The results have implications for both autoimmune and genetic myasthenias where anticholinesterase medication is a standard treatment.