Journal articles: 'Neuromuscular junction; Synapses; Myasthenic'

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Iyer, Shama R., Sameer B. Shah, and Richard M. Lovering. "The Neuromuscular Junction: Roles in Aging and Neuromuscular Disease." International Journal of Molecular Sciences 22, no. 15 (July 28, 2021): 8058. http://dx.doi.org/10.3390/ijms22158058.

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The neuromuscular junction (NMJ) is a specialized synapse that bridges the motor neuron and the skeletal muscle fiber and is crucial for conversion of electrical impulses originating in the motor neuron to action potentials in the muscle fiber. The consideration of contributing factors to skeletal muscle injury, muscular dystrophy and sarcopenia cannot be restricted only to processes intrinsic to the muscle, as data show that these conditions incur denervation-like findings, such as fragmented NMJ morphology and corresponding functional changes in neuromuscular transmission. Primary defects in the NMJ also influence functional loss in motor neuron disease, congenital myasthenic syndromes and myasthenia gravis, resulting in skeletal muscle weakness and heightened fatigue. Such findings underscore the role that the NMJ plays in neuromuscular performance. Regardless of cause or effect, functional denervation is now an accepted consequence of sarcopenia and muscle disease. In this short review, we provide an overview of the pathologic etiology, symptoms, and therapeutic strategies related to the NMJ. In particular, we examine the role of the NMJ as a disease modifier and a potential therapeutic target in neuromuscular injury and disease.

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Ohkawara, Bisei, Mikako Ito, and Kinji Ohno. "Secreted Signaling Molecules at the Neuromuscular Junction in Physiology and Pathology." International Journal of Molecular Sciences 22, no. 5 (February 28, 2021): 2455. http://dx.doi.org/10.3390/ijms22052455.

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Signal transduction at the neuromuscular junction (NMJ) is affected in many human diseases, including congenital myasthenic syndromes (CMS), myasthenia gravis, Lambert–Eaton myasthenic syndrome, Isaacs’ syndrome, Schwartz–Jampel syndrome, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. The NMJ is a prototypic cholinergic synapse between the motor neuron and the skeletal muscle. Synaptogenesis of the NMJ has been extensively studied, which has also been extrapolated to further understand synapse formation in the central nervous system. Studies of genetically engineered mice have disclosed crucial roles of secreted molecules in the development and maintenance of the NMJ. In this review, we focus on the secreted signaling molecules which regulate the clustering of acetylcholine receptors (AChRs) at the NMJ. We first discuss the signaling pathway comprised of neural agrin and its receptors, low-density lipoprotein receptor-related protein 4 (Lrp4) and muscle-specific receptor tyrosine kinase (MuSK). This pathway drives the clustering of acetylcholine receptors (AChRs) to ensure efficient signal transduction at the NMJ. We also discuss three secreted molecules (Rspo2, Fgf18, and connective tissue growth factor (Ctgf)) that we recently identified in the Wnt/β-catenin and fibroblast growth factors (FGF) signaling pathways. The three secreted molecules facilitate the clustering of AChRs by enhancing the agrin-Lrp4-MuSK signaling pathway.

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Khan, Muzamil Majid, Danilo Lustrino, Willian A. Silveira, Franziska Wild, Tatjana Straka, Yasmin Issop, Emily O’Connor, et al. "Sympathetic innervation controls homeostasis of neuromuscular junctions in health and disease." Proceedings of the National Academy of Sciences 113, no. 3 (January 5, 2016): 746–50. http://dx.doi.org/10.1073/pnas.1524272113.

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The distribution and function of sympathetic innervation in skeletal muscle have largely remained elusive. Here we demonstrate that sympathetic neurons make close contact with neuromuscular junctions and form a network in skeletal muscle that may functionally couple different targets including blood vessels, motor neurons, and muscle fibers. Direct stimulation of sympathetic neurons led to activation of muscle postsynaptic β2-adrenoreceptor (ADRB2), cAMP production, and import of the transcriptional coactivator peroxisome proliferator-activated receptor γ-coactivator 1α (PPARGC1A) into myonuclei. Electrophysiological and morphological deficits of neuromuscular junctions upon sympathectomy and in myasthenic mice were rescued by sympathicomimetic treatment. In conclusion, this study identifies the neuromuscular junction as a target of the sympathetic nervous system and shows that sympathetic input is crucial for synapse maintenance and function.

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Rodova, Marianna, Kevin F. Kelly, Michael VanSaun, Juliet M. Daniel, and Michael J. Werle. "Regulation of the Rapsyn Promoter by Kaiso and δ-Catenin." Molecular and Cellular Biology 24, no. 16 (August 15, 2004): 7188–96. http://dx.doi.org/10.1128/mcb.24.16.7188-7196.2004.

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ABSTRACT Rapsyn is a synapse-specific protein that is required for clustering acetylcholine receptors at the neuromuscular junction. Analysis of the rapsyn promoter revealed a consensus site for the transcription factor Kaiso within a region that is mutated in a subset of patients with congenital myasthenic syndrome. Kaiso is a POZ-zinc finger family transcription factor which recognizes the specific core consensus sequence CTGCNA (where N is any nucleotide). Previously, the only known binding partner for Kaiso was the cell adhesion cofactor, p120 catenin. Here we show that δ-catenin, a brain-specific member of the p120 catenin subfamily, forms a complex with Kaiso. Antibodies against Kaiso and δ-catenin recognize proteins in the nuclei of C2C12 myocytes and at the postsynaptic domain of the mouse neuromuscular junction. Endogenous Kaiso in C2C12 cells coprecipitates with the rapsyn promoter in vivo as shown by chromatin immunoprecipitation assay. Minimal promoter assays demonstrated that the rapsyn promoter can be activated by Kaiso and δ-catenin; this activation is apparently muscle specific. These results provide the first experimental evidence that rapsyn is a direct sequence-specific target of Kaiso and δ-catenin. We propose a new model of synapse-specific transcription that involves the interaction of Kaiso, δ-catenin, and myogenic transcription factors at the neuromuscular junction.

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Rodríguez Cruz, Pedro M., Judith Cossins, Eduardo de Paula Estephan, Francina Munell, Kathryn Selby, Michio Hirano, Reza Maroofin, et al. "The clinical spectrum of the congenital myasthenic syndrome resulting from COL13A1 mutations." Brain 142, no. 6 (May 13, 2019): 1547–60. http://dx.doi.org/10.1093/brain/awz107.

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Abstract Next generation sequencing techniques were recently used to show mutations in COL13A1 cause synaptic basal lamina-associated congenital myasthenic syndrome type 19. Animal studies showed COL13A1, a synaptic extracellular-matrix protein, is involved in the formation and maintenance of the neuromuscular synapse that appears independent of the Agrin-LRP4-MuSK-DOK7 acetylcholine receptor clustering pathway. Here, we report the phenotypic spectrum of 16 patients from 11 kinships harbouring homozygous or heteroallelic mutations in COL13A1. Clinical presentation was mostly at birth with hypotonia and breathing and feeding difficulties often requiring ventilation and artificial feeding. Respiratory crisis related to recurrent apnoeas, sometimes triggered by chest infections, were common early in life but resolved over time. The predominant pattern of muscle weakness included bilateral ptosis (non-fatigable in adulthood), myopathic facies and marked axial weakness, especially of neck flexion, while limb muscles were less involved. Other features included facial dysmorphism, skeletal abnormalities and mild learning difficulties. All patients tested had results consistent with abnormal neuromuscular transmission. Muscle biopsies were within normal limits or showed non-specific changes. Muscle MRI and serum creatine kinase levels were normal. In keeping with COL13A1 mutations affecting both synaptic structure and presynaptic function, treatment with 3,4-diaminopyridine and salbutamol resulted in motor and respiratory function improvement. In non-treated cases, disease severity and muscle strength improved gradually over time and several adults recovered normal muscle strength in the limbs. In summary, patients with COL13A1 mutations present mostly with severe early-onset myasthenic syndrome with feeding and breathing difficulties. Axial weakness is greater than limb weakness. Disease course improves gradually over time, which could be consistent with the less prominent role of COL13A1 once the neuromuscular junction is mature. This report emphasizes the role of collagens at the human muscle endplate and should facilitate the recognition of this disorder, which can benefit from pharmacological treatment.

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O’Connor, Emily, George Cairns, Sally Spendiff, David Burns, Stefan Hettwer, Armin Mäder, Juliane Müller, et al. "Modulation of Agrin and RhoA Pathways Ameliorates Movement Defects and Synapse Morphology in MYO9A-Depleted Zebrafish." Cells 8, no. 8 (August 7, 2019): 848. http://dx.doi.org/10.3390/cells8080848.

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Congenital myasthenic syndromes (CMS) are a group of rare, inherited disorders characterised by impaired function of the neuromuscular junction (NMJ). This is due to defects in one of the many proteins associated with the NMJ. In three patients with CMS, missense mutations in a gene encoding an unconventional myosin protein, MYO9A, were identified as likely causing their disorder. Preliminary studies revealed a potential involvement of the RhoA/ROCK pathway and of a key NMJ protein, agrin, in the pathophysiology of MYO9A-depletion. In this study, a CRISPR/Cas9 approach was used to generate genetic mutants of MYO9A zebrafish orthologues, myo9aa/ab, to expand and refine the morphological analysis of the NMJ. Injection of NT1654, a synthetic agrin fragment compound, improved NMJ structure and zebrafish movement in the absence of Myo9aa/ab. In addition, treatment of zebrafish with fasudil, a ROCK inhibitor, also provided improvements to the morphology of NMJs in early development, as well as rescuing movement defects, but not to the same extent as NT1654 and not at later time points. Therefore, this study highlights a role for MYO9A at the NMJ, the first unconventional myosin motor protein associated with a neuromuscular disease, and provides a potential mechanism of action of MYO9A-pathophysiology.

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Phillips, William D., and Angela Vincent. "Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms." F1000Research 5 (June 27, 2016): 1513. http://dx.doi.org/10.12688/f1000research.8206.1.

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Myasthenia gravis is an autoimmune disease of the neuromuscular junction (NMJ) caused by antibodies that attack components of the postsynaptic membrane, impair neuromuscular transmission, and lead to weakness and fatigue of skeletal muscle. This can be generalised or localised to certain muscle groups, and involvement of the bulbar and respiratory muscles can be life threatening. The pathogenesis of myasthenia gravis depends upon the target and isotype of the autoantibodies. Most cases are caused by immunoglobulin (Ig)G1 and IgG3 antibodies to the acetylcholine receptor (AChR). They produce complement-mediated damage and increase the rate of AChR turnover, both mechanisms causing loss of AChR from the postsynaptic membrane. The thymus gland is involved in many patients, and there are experimental and genetic approaches to understand the failure of immune tolerance to the AChR. In a proportion of those patients without AChR antibodies, antibodies to muscle-specific kinase (MuSK), or related proteins such as agrin and low-density lipoprotein receptor-related protein 4 (LRP4), are present. MuSK antibodies are predominantly IgG4 and cause disassembly of the neuromuscular junction by disrupting the physiological function of MuSK in synapse maintenance and adaptation. Here we discuss how knowledge of neuromuscular junction structure and function has fed into understanding the mechanisms of AChR and MuSK antibodies. Myasthenia gravis remains a paradigm for autoantibody-mediated conditions and these observations show how much there is still to learn about synaptic function and pathological mechanisms.

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Cruz, Pedro M. Rodríguez, Jacqueline Palace, and David Beeson. "Congenital myasthenic syndromes and the neuromuscular junction." Current Opinion in Neurology 27, no. 5 (October 2014): 566–75. http://dx.doi.org/10.1097/wco.0000000000000134.

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Tomàs, Josep, Manel M. Santafé, Maria A. Lanuza, Neus García, Nuria Besalduch, and Marta Tomàs. "Silent synapses in neuromuscular junction development." Journal of Neuroscience Research 89, no. 1 (September 20, 2010): 3–12. http://dx.doi.org/10.1002/jnr.22494.

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10

Plomp, Jaap J. "Trans-synaptic homeostasis at the myasthenic neuromuscular junction." Frontiers in Bioscience 22, no. 7 (2017): 1033–51. http://dx.doi.org/10.2741/4532.

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SCHUETZE, S. "Nerve-Muscle Synapses: The Vertebrate Neuromuscular Junction." Science 237, no. 4811 (July 10, 1987): 202–3. http://dx.doi.org/10.1126/science.237.4811.202.

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12

Cetin, Hakan, and Angela Vincent. "Pathogenic Mechanisms and Clinical Correlations in Autoimmune Myasthenic Syndromes." Seminars in Neurology 38, no. 03 (June 2018): 344–54. http://dx.doi.org/10.1055/s-0038-1660500.

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AbstractAutoimmune myasthenic syndromes are antibody-mediated disorders of the neuromuscular junction. Common antigenic targets are the acetylcholine receptor or muscle specific kinase (MuSK) in myasthenia gravis (MG) and the voltage-gated calcium channel in Lambert-Eaton myasthenic syndrome. There is evidence that antibodies directed against other antigens such as low-density lipoprotein receptor-related protein 4 (LRP4) are also involved in MG. The mechanisms by which various antibodies exert their pathogenic effect depend on the IgG subclass and also the epitope location on the antigens. These mechanisms are partly heterogeneous and include antigen degradation, complement activation, direct functional blocking, or disruption of protein–protein interactions. The neuromuscular junction is characterized by a structural and functional plasticity that is able to compensate for some of the neuromuscular junction defects. Here, we discuss the underlying pathogenic mechanisms of the different autoantibodies and correlate them with phenotypic features. The understanding of these elements should help guide the clinical management of patients with autoimmune myasthenic syndromes.

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Ohno, Kinji, and Andrew G. Engel. "Congenital myasthenic syndromes: Genetic defects of the neuromuscular junction." Current Neurology and Neuroscience Reports 2, no. 1 (February 2002): 78–88. http://dx.doi.org/10.1007/s11910-002-0057-7.

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McMacken, Grace M., Sally Spendiff, Roger G. Whittaker, Emily O’Connor, Rachel M. Howarth, Veronika Boczonadi, Rita Horvath, Clarke R. Slater, and Hanns Lochmüller. "Salbutamol modifies the neuromuscular junction in a mouse model of ColQ myasthenic syndrome." Human Molecular Genetics 28, no. 14 (April 1, 2019): 2339–51. http://dx.doi.org/10.1093/hmg/ddz059.

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Abstract The β-adrenergic agonists salbutamol and ephedrine have proven to be effective as therapies for human disorders of the neuromuscular junction, in particular many subsets of congenital myasthenic syndromes. However, the mechanisms underlying this clinical benefit are unknown and improved understanding of the effect of adrenergic signalling on the neuromuscular junction is essential to facilitate the development of more targeted therapies. Here, we investigated the effect of salbutamol treatment on the neuromuscular junction in the ColQ deficient mouse, a model of end-plate acetylcholinesterase deficiency. ColQ−/− mice received 7 weeks of daily salbutamol injection, and the effect on muscle strength and neuromuscular junction morphology was analysed. We show that salbutamol leads to a gradual improvement in muscle strength in ColQ−/− mice. In addition, the neuromuscular junctions of salbutamol treated mice showed significant improvements in several postsynaptic morphological defects, including increased synaptic area, acetylcholine receptor area and density, and extent of postjunctional folds. These changes occurred without alterations in skeletal muscle fibre size or type. These findings suggest that β-adrenergic agonists lead to functional benefit in the ColQ−/− mouse and to long-term structural changes at the neuromuscular junction. These effects are primarily at the postsynaptic membrane and may lead to enhanced neuromuscular transmission.

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Kumari, Sudha, Virginia Borroni, Ashutosh Chaudhry, Baron Chanda, Ramiro Massol, Satyajit Mayor, and Francisco J. Barrantes. "Nicotinic acetylcholine receptor is internalized via a Rac-dependent, dynamin-independent endocytic pathway." Journal of Cell Biology 181, no. 7 (June 30, 2008): 1179–93. http://dx.doi.org/10.1083/jcb.200709086.

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Endocytosis of the nicotinic acetylcholine receptor (AChR) is a proposed major mechanism of neuromodulation at neuromuscular junctions and in the pathology of synapses in the central nervous system. We show that binding of the competitive antagonist α-bungarotoxin (αBTX) or antibody-mediated cross-linking induces the internalization of cell surface AChR to late endosomes when expressed heterologously in Chinese hamster ovary cells or endogenously in C2C12 myocytes. Internalization occurs via sequestration of AChR–αBTX complexes in narrow, tubular, surface-connected compartments, which are indicated by differential surface accessibility of fluorescently tagged αBTX–AChR complexes to small and large molecules and real-time total internal reflection fluorescence imaging. Internalization occurs in the absence of clathrin, caveolin, or dynamin but requires actin polymerization. αBTX binding triggers c-Src phosphorylation and subsequently activates the Rho guanosine triphosphatase Rac1. Consequently, inhibition of c-Src kinase activity, Rac1 activity, or actin polymerization inhibits internalization via this unusual endocytic mechanism. This pathway may regulate AChR levels at ligand-gated synapses and in pathological conditions such as the autoimmune disease myasthenia gravis.

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Rodríguez Cruz, Pedro, Jacqueline Palace, and David Beeson. "The Neuromuscular Junction and Wide Heterogeneity of Congenital Myasthenic Syndromes." International Journal of Molecular Sciences 19, no. 6 (June 5, 2018): 1677. http://dx.doi.org/10.3390/ijms19061677.

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Beeson, David, Richard Webster, Judith Cossins, Daniel Lashley, Hayley Spearman, Susan Maxwell, Clarke R. Slater, John Newsom-Davis, Jacqueline Palace, and Angela Vincent. "Congenital Myasthenic Syndromes and the Formation of the Neuromuscular Junction." Annals of the New York Academy of Sciences 1132, no. 1 (June 2008): 99–103. http://dx.doi.org/10.1196/annals.1405.049.

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Lehky, T. J., F. M. Iwamoto, T. N. Kreisl, M. K. Floeter, and H. A. Fine. "Neuromuscular junction toxicity with tandutinib induces a myasthenic-like syndrome." Neurology 76, no. 3 (January 17, 2011): 236–41. http://dx.doi.org/10.1212/wnl.0b013e3182074a69.

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ENGEL, ANDREW G., KINJI OHNO, XIN-MING SHEN, and STEVEN M. SINE. "Congenital Myasthenic Syndromes: Multiple Molecular Targets at the Neuromuscular Junction." Annals of the New York Academy of Sciences 998, no. 1 (September 2003): 138–60. http://dx.doi.org/10.1196/annals.1254.016.

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Mathis, Stéphane, Laurent Magy, Philippe Corcia, Karima Ghorab, Laurence Richard, Jonathan Ciron, Mathilde Duchesne, and Jean-Michel Vallat. "Simultaneous Combined Myositis, Inflammatory Polyneuropathy, and Overlap Myasthenic Syndrome." Case Reports in Neurological Medicine 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/6108234.

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Immune-mediated neuromuscular disorders include pathologies of the peripheral nervous system, neuromuscular junction, and muscles. If overlap syndromes (or the association of almost two autoimmune disorders) are recognized, the simultaneous occurrence of several autoimmune neuromuscular disorders is rare. We describe two patients presenting the simultaneous occurrence of inflammatory neuropathy, myositis, and myasthenia gravis (with positive acetylcholine receptor antibodies). For each patient, we carried out a pathological analysis (nerve and muscle) and an electrophysiological study (and follow-up). To our knowledge, this is the first description of such a triple immune-mediated neuromuscular syndrome. We compared our observations with a few other cases of simultaneous diagnosis of two inflammatory neuromuscular disorders.

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Dwi ariningtyas, Ninuk, and Laily Irfana. "Pregnancy with Myasthenia Gravis." Qanun Medika - Medical Journal Faculty of Medicine Muhammadiyah Surabaya 4, no. 1 (January 27, 2020): 119. http://dx.doi.org/10.30651/jqm.v4i1.3678.

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ABSTRACTMyasthenia Gravis (MG) is a serious autoimmune disease, but now can be treated. Symptoms include weakness and fatigue in voluntary muscles caused by an autoantibody reaction to nicotinic acetylcholine receptor (AChR) at the post synapse of the neuromuscular junction. Pregnancy can affect autoimmune diseases so that pregnancy can aggravate MG disease. On the other hand it is also reported that pregnancy does not affect and can even improve MG disease. In this article, We report a 27-year-old woman who was diagnosed with myasthenia gravis that having a pregnancy. Initially she had no problems with pregnancy. Patients underwent pregnancy by taking the drug Mestinon four times daily and roborant. But entering the 33rd-34th week, the examination results showed that the pregnancy experienced oligohydramnios and Intrauterine Growth Retardation (IUGR), it was probably caused by malnutrition. Then we decided to end the patient's pregnancy with a Caesarean section. The operation went well, born to a baby boy / 2450grams / Apgar Score 5-7. Observation for one week the mother's condition continued to improve. Diplopia and weaknesses also improve. Likewise the baby showed a healthy condition. The patient was discharged while still taking MG drugs that had been previously consumed. This case report showed that pregnancy worsened MG disease, but MG did not affect pregnancy.Keywords : Pregnancy, Myasthenia Gravis

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Robberecht, W., J. Bednarik, P. Bourgeois, J. van Hees, and H. Carton. "Myasthenic Syndrome Caused by Direct Effect of Chloroquine on Neuromuscular Junction." Archives of Neurology 46, no. 4 (April 1, 1989): 464–68. http://dx.doi.org/10.1001/archneur.1989.00520400124033.

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Vrbova, G., and M. Lowrie. "Role of Activity in Developing Synapses. Search for Molecular Mechanisms." Physiology 4, no. 2 (April 1, 1989): 75–78. http://dx.doi.org/10.1152/physiologyonline.1989.4.2.75.

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The involvement of activity in synapse elimination at the neuromuscular junction is discussed, and a mechanism is proposed based on the molecular processes that are a consequence of normal neuromuscular activity.

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Newsom-Davis, John. "Autoantibody-Mediated Channelopathies at the Neuromuscular Junction." Neuroscientist 3, no. 5 (September 1997): 337–46. http://dx.doi.org/10.1177/107385849700300515.

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The neuromuscular junction is vulnerable to antibody-mediated autoimmune attack, probably because it lacks the protection of the blood-brain barrier. This review focuses on three disorders: myasthenia gravis (MG) and the Lambert-Eaton myasthenic syndrome (LEMS), in both of which there is fatiguable muscle weakness, and acquired neuromyotonia (ANMT), in which hyperexcitable peripheral nerves lead to continuous muscle fiber activity and sometimes parasthesias. Each can occur as a paraneoplastic disorder (thymoma in MG and ANMT, and small cell lung cancer in LEMS). The clinical abnormalities are improved following plasmapheresis (which removes circulating antibodies), and injection of experimental animals with immunoglobulins of patients transfers the pathophysiological changes. The ion channel targets in these three disorders are the muscle acetylcholine receptor (a ligand-gated cation channel) in MG, nerve terminal and autonomic voltage-gated calcium channels in LEMS, and peripheral nerve voltage-gated potassium channels in ANMT. The autoantibody attack results in a reduced number of functional channels. Each of the autoantibodies can be detected in serum by immunoassay. These discoveries have allowed new approaches to treatment and suggest that there may be other undiscovered antibody-mediated ion channelopathies. NEUROSCIENTIST 3:337–346, 1997

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Giannoccaro, Maria Pia, Patrizia Avoni, and Rocco Liguori. "Presynaptic Paraneoplastic Disorders of the Neuromuscular Junction: An Update." Brain Sciences 11, no. 8 (August 3, 2021): 1035. http://dx.doi.org/10.3390/brainsci11081035.

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The neuromuscular junction (NMJ) is the target of a variety of immune-mediated disorders, usually classified as presynaptic and postsynaptic, according to the site of the antigenic target and consequently of the neuromuscular transmission alteration. Although less common than the classical autoimmune postsynaptic myasthenia gravis, presynaptic disorders are important to recognize due to the frequent association with cancer. Lambert Eaton myasthenic syndrome is due to a presynaptic failure to release acetylcholine, caused by antibodies to the presynaptic voltage-gated calcium channels. Acquired neuromyotonia is a condition characterized by nerve hyperexcitability often due to the presence of antibodies against proteins associated with voltage-gated potassium channels. This review will focus on the recent developments in the autoimmune presynaptic disorders of the NMJ.

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Wong, K., S. Karunanithi, and H. L. Atwood. "Quantal Unit Populations at the DrosophilaLarval Neuromuscular Junction." Journal of Neurophysiology 82, no. 3 (September 1, 1999): 1497–511. http://dx.doi.org/10.1152/jn.1999.82.3.1497.

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Focal extracellular recording at visualized boutons of the Drosophila larval neuromuscular junction was used to determine frequency and time course of the spontaneously occurring quantal events. When simultaneous intracellular recordings from the innervated muscle cell were made, more than one class of quantal event occurred at some of the individual boutons. “True” signals (arising at the bouton within the focal macropatch electrode) were often contaminated by additional signals generated outside the lumen of the focal electrode. Inclusion of these contaminating signals gave spuriously low values for relative amplitude, and spuriously high values for spontaneous quantal emission, for the synapses within the focal electrode. The contaminating signals, which appeared to be conducted along the subsynaptic reticulum surrounding the nerve terminals, generally were characterized by relatively small extracellular signals associated with normal intracellular events in the muscle fiber. From plots of simultaneous extracellular and intracellular recordings, the individual data points were classified according to the angles they subtended with the x axis (extracellular signal axis). Statistical procedures were developed to separate the true signals and contaminants with a high level of confidence. Populations of quantal events were found to be well described by Gaussian mixtures of two or three components, one of which could be characterized as the true signal population. Separation of signals from contaminants provides a basis for improving the estimates of quantal size and spontaneous frequency for the synapses sampled by the focal extracellular electrode.

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Varoqueaux, Frédérique, Michèle S. Sons, Jaap J. Plomp, and Nils Brose. "Aberrant Morphology and Residual Transmitter Release at the Munc13-Deficient Mouse Neuromuscular Synapse." Molecular and Cellular Biology 25, no. 14 (July 2005): 5973–84. http://dx.doi.org/10.1128/mcb.25.14.5973-5984.2005.

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ABSTRACT In cultured hippocampal neurons, synaptogenesis is largely independent of synaptic transmission, while several accounts in the literature indicate that synaptogenesis at cholinergic neuromuscular junctions in mammals appears to partially depend on synaptic activity. To systematically examine the role of synaptic activity in synaptogenesis at the neuromuscular junction, we investigated neuromuscular synaptogenesis and neurotransmitter release of mice lacking all synaptic vesicle priming proteins of the Munc13 family. Munc13-deficient mice are completely paralyzed at birth and die immediately, but form specialized neuromuscular endplates that display typical synaptic features. However, the distribution, number, size, and shape of these synapses, as well as the number of motor neurons they originate from and the maturation state of muscle cells, are profoundly altered. Surprisingly, Munc13-deficient synapses exhibit significantly increased spontaneous quantal acetylcholine release, although fewer fusion-competent synaptic vesicles are present and nerve stimulation-evoked secretion is hardly elicitable and strongly reduced in magnitude. We conclude that the residual transmitter release in Munc13-deficient mice is not sufficient to sustain normal synaptogenesis at the neuromuscular junction, essentially causing morphological aberrations that are also seen upon total blockade of neuromuscular transmission in other genetic models. Our data confirm the importance of Munc13 proteins in synaptic vesicle priming at the neuromuscular junction but indicate also that priming at this synapse may differ from priming at glutamatergic and γ-aminobutyric acid-ergic synapses and is partly Munc13 independent. Thus, non-Munc13 priming proteins exist at this synapse or vesicle priming occurs in part spontaneously: i.e., without dedicated priming proteins in the release machinery.

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McConkey, P. P., and A. J. Mullens. "Congenital Myasthenic Syndrome: A Rare, Potentially Treatable Cause of Respiratory Failure in a “Floppy” Infant." Anaesthesia and Intensive Care 28, no. 1 (February 2000): 82–86. http://dx.doi.org/10.1177/0310057x0002800116.

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A four-month-old infant, thought to suffer from cerebral palsy, presented with respiratory failure on the background of a gradually deteriorating general level of function. Whilst being ventilated in intensive care he was noted to have severe muscle weakness. A disorder of the neuromuscular junction was suspected and he was subsequently demonstrated to have a congenital myasthenic syndrome. Anticholinesterase therapy produced a dramatic recovery. The congenital myasthenic syndromes and the diagnosis of a “floppy baby” are briefly reviewed.

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Beeson, D. M. W. "M.I.2 Congenital myasthenic syndromes and the formation of the neuromuscular junction." Neuromuscular Disorders 18, no. 9-10 (October 2008): 779. http://dx.doi.org/10.1016/j.nmd.2008.06.192.

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SONS, M. S., M. VERHAGE, and J. J. PLOMP. "Role of Munc18-1 in Synaptic Plasticity at the Myasthenic Neuromuscular Junction." Annals of the New York Academy of Sciences 998, no. 1 (September 2003): 404–6. http://dx.doi.org/10.1196/annals.1254.052.

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Martinez-Pena y Valenzuela, Isabel, and Mohammed Akaaboune. "Acetylcholinesterase Mobility and Stability at the Neuromuscular Junction of Living Mice." Molecular Biology of the Cell 18, no. 8 (August 2007): 2904–11. http://dx.doi.org/10.1091/mbc.e07-02-0093.

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Acetylcholinesterase (AChE) is an enzyme that terminates acetylcholine neurotransmitter function at the synaptic cleft of cholinergic synapses. However, the mechanism by which AChE number and density are maintained at the synaptic cleft is poorly understood. In this work, we used fluorescence recovery after photobleaching, photo-unbinding, and quantitative fluorescence imaging to investigate the surface mobility and stability of AChE at the adult innervated neuromuscular junction of living mice. In wild-type synapses, we found that nonsynaptic (perisynaptic and extrasynaptic) AChEs are mobile and gradually recruited into synaptic sites and that most of the trapped AChEs come from the perijunctional pool. Selective labeling of a subset of synaptic AChEs within the synapse by using sequential unbinding and relabeling with different colors of streptavidin followed by time-lapse imaging showed that synaptic AChEs are nearly immobile. At neuromuscular junctions of mice deficient in α-dystrobrevin, a component of the dystrophin glycoprotein complex, we found that the density and distribution of synaptic AChEs are profoundly altered and that the loss rate of AChE significantly increased. These results demonstrate that nonsynaptic AChEs are mobile, whereas synaptic AChEs are more stable, and that α-dystrobrevin is important for controlling the density and stability of AChEs at neuromuscular synapses.

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Akaaboune, Mohammed, Susan M. Culican, Stephen G. Turney, and Jeff W. Lichtman. "Rapid and Reversible Effects of Activity on Acetylcholine Receptor Density at the Neuromuscular Junction in Vivo." Science 286, no. 5439 (October 15, 1999): 503–7. http://dx.doi.org/10.1126/science.286.5439.503.

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Quantitative fluorescence imaging was used to study the regulation of acetylcholine receptor (AChR) number and density at neuromuscular junctions in living adult mice. At fully functional synapses, AChRs have a half-life of about 14 days. However, 2 hours after neurotransmission was blocked, the half-life of the AChRs was now less than a day; the rate was 25 times faster than before. Most of the lost receptors were not quickly replaced. Direct muscle stimulation or restoration of synaptic transmission inhibited this process. AChRs that were removed from nonfunctional synapses resided for hours in the perijunctional membrane before being locally internalized. Dispersed AChRs could also reaggregate at the junction once neurotransmission was restored. The rapid and reversible alterations in AChR density at the neuromuscular junction in vivo parallel changes thought to occur in the central nervous system at synapses undergoing potentiation and depression.

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Barbeau, Susie, Julie Tahraoui-Bories, Claire Legay, and Cécile Martinat. "Building neuromuscular junctions in vitro." Development 147, no. 22 (November 15, 2020): dev193920. http://dx.doi.org/10.1242/dev.193920.

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ABSTRACTThe neuromuscular junction (NMJ) has been the model of choice to understand the principles of communication at chemical synapses. Following groundbreaking experiments carried out over 60 years ago, many studies have focused on the molecular mechanisms underlying the development and physiology of these synapses. This Review summarizes the progress made to date towards obtaining faithful models of NMJs in vitro. We provide a historical approach discussing initial experiments investigating NMJ development and function from Xenopus to mice, the creation of chimeric co-cultures, in vivo approaches and co-culture methods from ex vivo and in vitro derived cells, as well as the most recent developments to generate human NMJs. We discuss the benefits of these techniques and the challenges to be addressed in the future for promoting our understanding of development and human disease.

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Müller, Juliane S., Violeta Mihaylova, Angela Abicht, and Hanns Lochmüller. "Congenital myasthenic syndromes: spotlight on genetic defects of neuromuscular transmission." Expert Reviews in Molecular Medicine 9, no. 22 (August 2007): 1–20. http://dx.doi.org/10.1017/s1462399407000427.

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AbstractThe neuromuscular junction (NMJ) is a complex structure that efficiently communicates the electrical impulse from the motor neuron to the skeletal muscle to induce muscle contraction. Genetic and autoimmune disorders known to compromise neuromuscular transmission are providing further insights into the complexities of NMJ function. Congenital myasthenic syndromes (CMSs) are a genetically and phenotypically heterogeneous group of rare hereditary disorders affecting neuromuscular transmission. The understanding of the molecular basis of the different types of CMSs has evolved rapidly in recent years. Mutations were first identified in the subunits of the nicotinic acetylcholine receptor (AChR), but now mutations in ten different genes – encoding post-, pre- or synaptic proteins – are known to cause CMSs. Pathogenic mechanisms leading to an impaired neuromuscular transmission modify AChRs or endplate structure or lead to decreased acetylcholine synthesis and release. However, the genetic background of many CMS forms is still unresolved. A precise molecular classification of CMS type is of paramount importance for the diagnosis, counselling and therapy of a patient, as different drugs may be beneficial or deleterious depending on the molecular background of the particular CMS.

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Lorenzoni, Paulo José, Cláudia Suemi Kamoi Kay, Lineu Cesar Werneck, and Rosana Herminia Scola. "Lambert-Eaton myasthenic syndrome: the 60th anniversary of Eaton and Lambert's pioneering article." Arquivos de Neuro-Psiquiatria 76, no. 2 (February 2018): 124–26. http://dx.doi.org/10.1590/0004-282x20170194.

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ABSTRACT This historical review describes the contribution of Drs. Lee M. Eaton and Edward H. Lambert to the diagnosis of myasthenic syndrome on the 60th anniversary of their pioneering article (JAMA 1957) on the disease. There are important landmarks in their article on a disorder of the neuromuscular junction associated with thoracic neoplasm and the electrophysiological criteria for Lambert-Eaton myasthenic syndrome (LEMS). After 60 years, the main electrophysiological criteria described in Eaton and Lambert's pioneering article are still currently useful in the diagnosis of LEMS.

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Wojtowicz, J. M., L. Marin, and H. L. Atwood. "Synaptic restructuring during long-term facilitation at the crayfish neuromuscular junction." Canadian Journal of Physiology and Pharmacology 67, no. 2 (February 1, 1989): 167–71. http://dx.doi.org/10.1139/y89-028.

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Long-term facilitation was induced by 20-Hz stimulation of the motor axon innervating the opener muscle of the crayfish, Procambarus clarkii. Excitatory postsynaptic potentials remained potentiated for several hours after stimulation. Structural correlates of potentiation were sought. Nerve terminals of the motor axon were fixed for electron microscopy in unstimulated preparations (controls), and during and after 20-Hz stimulation. Synapses were reconstructed from micrographs obtained from serial sections. Synaptic contact area and the number of vesicles at the presynaptic membrane did not change after 20-Hz stimulation, but the latter decreased during stimulation. Presynaptic dense bars ("active zones") decreased in number during and increased after stimulation, while perforated synapses increased after stimulation. Modification of presynaptic structures occurs rapidly and may be linked to long-lasting changes in quantal content of transmission.Key words: facilitation, plasticity, release site, synaptic vesicle, transmitter release.

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Wang, Meng, Hua Wen, and Paul Brehm. "Function of Neuromuscular Synapses in the Zebrafish Choline-Acetyltransferase Mutant bajan." Journal of Neurophysiology 100, no. 4 (October 2008): 1995–2004. http://dx.doi.org/10.1152/jn.90517.2008.

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We have identified a zebrafish mutant line, bajan, in which compromised motility and fatigue result from a point mutation in the gene coding choline acetyltransferase (ChAT), the enzyme responsible for acetylcholine (ACh) synthesis. Although the mutation predicts loss of ChAT function, bajan inexplicably retains low levels of neuromuscular transmission. We exploited this residual activity and determined the consequences for synaptic function. The attenuated synaptic responses were a direct consequence of a decrease in both resting mean quantal size and quantal content. To replicate behavioral fatigue in swimming, motorneurons were stimulated at high frequencies. A prominent reduction in quantal content, reflecting vesicle depletion, was coincident with a small additional reduction in quantal size. In humans, defective ChAT leads to episodic apnea, a form of congenital myasthenic syndrome characterized by use-dependent fatigue. In contrast to bajan, however, afflicted individuals exhibit a normal resting quantal size and quantal content. The fatigue in humans results from a pronounced long-lasting drop in quantal size with little or no change in quantal content. These differences have important implications for interpreting fatigue as well as on understanding the impact of ACh availability on vesicle filling and recycling.

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DePew, Alison T., and Timothy J. Mosca. "Conservation and Innovation: Versatile Roles for LRP4 in Nervous System Development." Journal of Developmental Biology 9, no. 1 (March 14, 2021): 9. http://dx.doi.org/10.3390/jdb9010009.

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As the nervous system develops, connections between neurons must form to enable efficient communication. This complex process of synaptic development requires the coordination of a series of intricate mechanisms between partner neurons to ensure pre- and postsynaptic differentiation. Many of these mechanisms employ transsynaptic signaling via essential secreted factors and cell surface receptors to promote each step of synaptic development. One such cell surface receptor, LRP4, has emerged as a synaptic organizer, playing a critical role in conveying extracellular signals to initiate diverse intracellular events during development. To date, LRP4 is largely known for its role in development of the mammalian neuromuscular junction, where it functions as a receptor for the synaptogenic signal Agrin to regulate synapse development. Recently however, LRP4 has emerged as a synapse organizer in the brain, where new functions for the protein continue to arise, adding further complexity to its already versatile roles. Additional findings indicate that LRP4 plays a role in disorders of the nervous system, including myasthenia gravis, amyotrophic lateral sclerosis, and Alzheimer’s disease, demonstrating the need for further study to understand disease etiology. This review will highlight our current knowledge of how LRP4 functions in the nervous system, focusing on the diverse developmental roles and different modes this essential cell surface protein uses to ensure the formation of robust synaptic connections.

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McMacken, G., D. Cox, A. Roos, J. Müller, R. Whittaker, and H. Lochmüller. "Adrenergic agonists modulate neuromuscular junction formation in zebrafish models of human myasthenic syndromes." Neuromuscular Disorders 28 (April 2018): S28. http://dx.doi.org/10.1016/s0960-8966(18)30373-0.

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Mihailovska, Eva, Marianne Raith, Rocio G. Valencia, Irmgard Fischer, Mumna Al Banchaabouchi, Ruth Herbst, and Gerhard Wiche. "Neuromuscular synapse integrity requires linkage of acetylcholine receptors to postsynaptic intermediate filament networks via rapsyn–plectin 1f complexes." Molecular Biology of the Cell 25, no. 25 (December 15, 2014): 4130–49. http://dx.doi.org/10.1091/mbc.e14-06-1174.

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Mutations in the cytolinker protein plectin lead to grossly distorted morphology of neuromuscular junctions (NMJs) in patients suffering from epidermolysis bullosa simplex (EBS)-muscular dystrophy (MS) with myasthenic syndrome (MyS). Here we investigated whether plectin contributes to the structural integrity of NMJs by linking them to the postsynaptic intermediate filament (IF) network. Live imaging of acetylcholine receptors (AChRs) in cultured myotubes differentiated ex vivo from immortalized plectin-deficient myoblasts revealed them to be highly mobile and unable to coalesce into stable clusters, in contrast to wild-type cells. We found plectin isoform 1f (P1f) to bridge AChRs and IFs via direct interaction with the AChR-scaffolding protein rapsyn in an isoform-specific manner; forced expression of P1f in plectin-deficient cells rescued both compromised AChR clustering and IF network anchoring. In conditional plectin knockout mice with gene disruption in muscle precursor/satellite cells (Pax7-Cre/cKO), uncoupling of AChRs from IFs was shown to lead to loss of postsynaptic membrane infoldings and disorganization of the NMJ microenvironment, including its invasion by microtubules. In their phenotypic behavior, mutant mice closely mimicked EBS-MD-MyS patients, including impaired body balance, severe muscle weakness, and reduced life span. Our study demonstrates that linkage to desmin IF networks via plectin is crucial for formation and maintenance of AChR clusters, postsynaptic NMJ organization, and body locomotion.

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Gilhus, Nils Erik. "Lambert-Eaton Myasthenic Syndrome; Pathogenesis, Diagnosis, and Therapy." Autoimmune Diseases 2011 (2011): 1–5. http://dx.doi.org/10.4061/2011/973808.

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Lambert-Eaton Myasthenic Syndrome (LEMS) is a rare disease with a well-characterized pathogenesis. In 50% of the patients, LEMS is a paraneoplastic manifestation and caused by a small cell lung carcinoma (SCLC). Both LEMS patients with SCLC and those without this tumour have in 85% of cases pathogenetic antibodies of very high LEMS specificity against voltage-gated calcium channels (VGCCs) in the cell membrane of the presynaptic motor nerve terminal. Better understanding of LEMS pathogenesis has lead to targeted symptomatic therapy aimed at the neuromuscular junction and to semispecific immuno-suppression. For SCLC LEMS, tumour therapy is essential.

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O'Leary, Debra A., Peter G. Noakes, Nick A. Lavidis, Ismail Kola, Paul J. Hertzog, and Sika Ristevski. "Targeting of the ETS Factor Gabpα Disrupts Neuromuscular Junction Synaptic Function." Molecular and Cellular Biology 27, no. 9 (February 26, 2007): 3470–80. http://dx.doi.org/10.1128/mcb.00659-06.

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ABSTRACT The GA-binding protein (GABP) transcription factor has been shown in vitro to regulate the expression of the neuromuscular proteins utrophin, acetylcholine esterase, and acetylcholine receptor subunits δ and ε through the N-box promoter motif (5′-CCGGAA-3′), but its in vivo function remains unknown. A single point mutation within the N-box of the gene encoding the acetylcholine receptor ε subunit has been identified in several patients suffering from postsynaptic congenital myasthenic syndrome, implicating the GA-binding protein in neuromuscular function and disease. Since conventional gene targeting results in an embryonic-lethal phenotype, we used conditional targeting to investigate the role of GABPα in neuromuscular junction and skeletal muscle development. The diaphragm and soleus muscles from mutant mice display alterations in morphology and distribution of acetylcholine receptor clusters at the neuromuscular junction and neurotransmission properties consistent with reduced receptor function. Furthermore, we confirmed decreased expression of the acetylcholine receptor ε subunit and increased expression of the γ subunit in skeletal muscle tissues. Therefore, the GABP transcription factor aids in the structural formation and function of neuromuscular junctions by regulating the expression of postsynaptic genes.

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Bhagat, Hemant, Vinod Grover, and Kiran Jangra. "What is optimal in patients with myasthenic crisis: Invasive or non-invasive ventilation?" Journal of Neuroanaesthesiology and Critical Care 01, no. 02 (May 2014): 116–20. http://dx.doi.org/10.4103/2348-0548.130388.

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AbstractMyasthenia gravis is an immune disorder involving the neuromuscular junction. The consequent weakness of respiratory muscles leads to variable disorders of ventilation in patients with myasthenia gravis. This article reviews the options of invasive and non-invasive ventilation in patients with advanced form of the disease.

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Jones, Ross A., Caitlan D. Reich, Kosala N. Dissanayake, Fanney Kristmundsdottir, Gordon S. Findlater, Richard R. Ribchester, Martin W. Simmen, and Thomas H. Gillingwater. "NMJ-morph reveals principal components of synaptic morphology influencing structure–function relationships at the neuromuscular junction." Open Biology 6, no. 12 (December 2016): 160240. http://dx.doi.org/10.1098/rsob.160240.

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The ability to form synapses is one of the fundamental properties required by the mammalian nervous system to generate network connectivity. Structural and functional diversity among synaptic populations is a key hallmark of network diversity, and yet we know comparatively little about the morphological principles that govern variability in the size, shape and strength of synapses. Using the mouse neuromuscular junction (NMJ) as an experimentally accessible model synapse, we report on the development of a robust, standardized methodology to facilitate comparative morphometric analysis of synapses (‘NMJ-morph’). We used NMJ-morph to generate baseline morphological reference data for 21 separate pre- and post-synaptic variables from 2160 individual NMJs belonging to nine anatomically distinct populations of synapses, revealing systematic differences in NMJ morphology between defined synaptic populations. Principal components analysis revealed that overall NMJ size and the degree of synaptic fragmentation, alongside pre-synaptic axon diameter, were the most critical parameters in defining synaptic morphology. ‘Average’ synaptic morphology was remarkably conserved between comparable synapses from the left and right sides of the body. Systematic differences in synaptic morphology predicted corresponding differences in synaptic function that were supported by physiological recordings, confirming the robust relationship between synaptic size and strength.

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Pulido, Camila, and Alain Marty. "Quantal Fluctuations in Central Mammalian Synapses: Functional Role of Vesicular Docking Sites." Physiological Reviews 97, no. 4 (October 1, 2017): 1403–30. http://dx.doi.org/10.1152/physrev.00032.2016.

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Quantal fluctuations are an integral part of synaptic signaling. At the frog neuromuscular junction, Bernard Katz proposed that quantal fluctuations originate at “reactive sites” where specific structures of the presynaptic membrane interact with synaptic vesicles. However, the physical nature of reactive sites has remained unclear, both at the frog neuromuscular junction and at central synapses. Many central synapses, called simple synapses, are small structures containing a single presynaptic active zone and a single postsynaptic density of receptors. Several lines of evidence indicate that simple synapses may release several synaptic vesicles in response to a single action potential. However, in some synapses at least, each release event activates a significant fraction of the postsynaptic receptors, giving rise to a sublinear relation between vesicular release and postsynaptic current. Partial receptor saturation as well as synaptic jitter gives to simple synapse signaling the appearance of a binary process. Recent investigations of simple synapses indicate that the number of released vesicles follows binomial statistics, with a maximum reflecting the number of docking sites present in the active zone. These results suggest that at central synapses, vesicular docking sites represent the reactive sites proposed by Katz. The macromolecular architecture and molecular composition of docking sites are presently investigated with novel combinations of techniques. It is proposed that variations in docking site numbers are central in defining intersynaptic variability and that docking site occupancy is a key parameter regulating short-term synaptic plasticity.

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Souza, Paulo Victor Sgobbi de, Gabriel Novaes de Rezende Batistella, Valéria Cavalcante Lino, Wladimir Bocca Vieira de Rezende Pinto, Marcelo Annes, and Acary Souza Bulle Oliveira. "Clinical and genetic basis of congenital myasthenic syndromes." Arquivos de Neuro-Psiquiatria 74, no. 9 (September 2016): 750–60. http://dx.doi.org/10.1590/0004-282x20160106.

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ABSTRACT Neuromuscular junction disorders represent a wide group of neurological diseases characterized by weakness, fatigability and variable degrees of appendicular, ocular and bulbar musculature involvement. Its main group of disorders includes autoimmune conditions, such as autoimmune acquired myasthenia gravis and Lambert-Eaton syndrome. However, an important group of diseases include congenital myasthenic syndromes with a genetic and sometimes hereditary basis that resemble and mimick many of the classic myasthenia neurological manifestations, but also have different presentations, which makes them a complex clinical, therapeutic and diagnostic challenge for most clinicians. We conducted a wide review of congenital myasthenic syndromes in their clinical, genetic and therapeutic aspects.

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Nanou, Evanthia, Jin Yan, Nicholas P. Whitehead, Min Jeong Kim, Stanley C. Froehner, Todd Scheuer, and William A. Catterall. "Altered short-term synaptic plasticity and reduced muscle strength in mice with impaired regulation of presynaptic CaV2.1 Ca2+ channels." Proceedings of the National Academy of Sciences 113, no. 4 (January 11, 2016): 1068–73. http://dx.doi.org/10.1073/pnas.1524650113.

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Facilitation and inactivation of P/Q-type calcium (Ca2+) currents through the regulation of voltage-gated Ca2+ (CaV) 2.1 channels by Ca2+ sensor (CaS) proteins contributes to the facilitation and rapid depression of synaptic transmission in cultured neurons that transiently express CaV2.1 channels. To examine the modulation of endogenous CaV2.1 channels by CaS proteins in native synapses, we introduced a mutation (IM-AA) into the CaS protein-binding site in the C-terminal domain of CaV2.1 channels in mice, and tested synaptic facilitation and depression in neuromuscular junction synapses that use exclusively CaV2.1 channels for Ca2+ entry that triggers synaptic transmission. Even though basal synaptic transmission was unaltered in the neuromuscular synapses in IM-AA mice, we found reduced short-term facilitation in response to paired stimuli at short interstimulus intervals in IM-AA synapses. In response to trains of action potentials, we found increased facilitation at lower frequencies (10–30 Hz) in IM-AA synapses accompanied by slowed synaptic depression, whereas synaptic facilitation was reduced at high stimulus frequencies (50–100 Hz) that would induce strong muscle contraction. As a consequence of altered regulation of CaV2.1 channels, the hindlimb tibialis anterior muscle in IM-AA mice exhibited reduced peak force in response to 50 Hz stimulation and increased muscle fatigue. The IM-AA mice also had impaired motor control, exercise capacity, and grip strength. Taken together, our results indicate that regulation of CaV2.1 channels by CaS proteins is essential for normal synaptic plasticity at the neuromuscular junction and for muscle strength, endurance, and motor coordination in mice in vivo.

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Wojtowicz, J. M., and H. L. Atwood. "Long-term facilitation alters transmitter releasing properties at the crayfish neuromuscular junction." Journal of Neurophysiology 55, no. 3 (March 1, 1986): 484–98. http://dx.doi.org/10.1152/jn.1986.55.3.484.

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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.

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Fuhrer, Christian, and Kyung-Hye Huh. "Clustering of Nicotinic Acetylcholine Receptors: From the Neuromuscular Junction to Interneuronal Synapses." Molecular Neurobiology 25, no. 1 (2002): 079–112. http://dx.doi.org/10.1385/mn:25:1:079.

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Eguchi, Takahiro, Tohru Tezuka, Sadanori Miyoshi, and Yuji Yamanashi. "Postnatal knockdown ofdok-7gene expression in mice causes structural defects in neuromuscular synapses and myasthenic pathology." Genes to Cells 21, no. 6 (April 18, 2016): 670–76. http://dx.doi.org/10.1111/gtc.12370.

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Journal articles on the topic 'Neuromuscular junction; Synapses; Myasthenic'

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