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Gary C. Sieck - One of the best experts on this subject based on the ideXlab platform.
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Neurotrophins improve Neuromuscular Transmission in the adult rat diaphragm.
Muscle & Nerve, 2004Co-Authors: Carlos B. Mantilla, W. Z. Zhan, Gary C. SieckAbstract:Neurotrophins modulate acute and sustained synaptic plasticity. In cultured Xenopus laevis Neuromuscular junctions, neurotrophins improve Neuromuscular Transmission. Whether this influence exists at the mammalian Neuromuscular junction is unknown. We hypothesized that neurotrophins improve Neuromuscular Transmission at Neuromuscular junctions of adult rat diaphragm muscle fibers. A diaphragm muscle-phrenic nerve preparation was used to determine the effects of brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4) and K252a [tyrosine kinase (Trk) receptor inhibitor] on the extent of Neuromuscular Transmission failure induced by repetitive nerve stimulation. We found significant enhancement of Neuromuscular Transmission with BDNF or NT-4 treatment, whereas K252a treatment worsened Neuromuscular Transmission. In contrast, diaphragm muscle contractile and fatigue properties were unaffected by neurotrophin or K252a treatment. These results demonstrate that BDNF and NT-4 improve synaptic Transmission in the adult rat diaphragm muscle, likely in a Trk-dependent fashion. Neurotrophins may constitute a novel therapeutic target to improve Neuromuscular function in the diaphragm.
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Regulation of Neuromuscular Transmission by neurotrophins.
Sheng li xue bao : [Acta physiologica Sinica], 2003Co-Authors: Wen Zhi Zhan, Carlos B. Mantilla, Gary C. SieckAbstract:Motor units comprise a motoneuron and the muscle fibers it innervates. Neuromuscular Transmission is tightly regulated to match the activity of individual motor units. Activity-dependent release of neuromodulators at the Neuromuscular junction (NMJ) determines the efficacy of Transmission. The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) are produced by motoneurons and muscle fibers, and their release by skeletal muscle is regulated by muscle activity. BDNF and NT-4 enhance both spontaneous and evoked synaptic Transmission at NMJs via activation of the tyrosine kinase receptor B (TrkB). Improvements in Neuromuscular Transmission may result from increased release of synaptic vesicles, either by presynaptic alterations in Ca(2+) transients or facilitated vesicular exocytosis. In fact, BDNF potentiates intracellular Ca(2+) release presynaptically and BDNF-induced TrkB activation also results in phosphorylation of synapsin I via mitogen activated protein kinase, which increases the number of synaptic vesicles available for release. Neurotrophins may also regulate synaptic Transmission at the NMJ by increasing local release of neuregulin or other nerve-derived modulators. We review recent studies on the regulation of Neuromuscular Transmission, the motor unit-specific properties of NMJs and the effects of neurotrophins on synaptic efficacy at the NMJ.
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Differential susceptibility of diaphragm muscle fibers to Neuromuscular Transmission failure.
Journal of Applied Physiology, 1993Co-Authors: Bruce D. Johnson, Gary C. SieckAbstract:The pattern of glycogen utilization was used to determine whether various muscle fiber types in the rat diaphragm are differentially susceptible to Neuromuscular Transmission failure. Muscle segments from the midcostal region were repetitively stimulated directly or via the phrenic nerve at 10 or 75 Hz. Muscle fiber types were classified histochemically as type I, IIa, or IIb. The amount of muscle fiber glycogen depletion with direct stimulation depended on stimulation rate (75 Hz > 10 Hz) and fiber type (IIb > IIa > I). However, with nerve stimulation, muscle fiber glycogen depletion did not display the same dependency on stimulation rate (10 Hz > 75 Hz), although with stimulation at 10 Hz, the same rank order of fiber depletion was observed (IIb > IIa > I). This rank order of depletion was reversed (I > IIa > IIb) during repetitive stimulation of the nerve at 75 Hz. By intermittently stimulating the muscle directly during continuous nerve stimulation, we determined that Neuromuscular Transmission failure contributed significantly to the force decline after 2 min of stimulation at 75 Hz but relatively little to the force decline after 2 min of stimulation at 10 Hz. A significantly greater fraction of the force decline could be attributed to Neuromuscular Transmission failure with repetitive bouts of stimulation at 10 Hz. We conclude that Neuromuscular Transmission failure causes a significant portion of the force decline after 8 min of stimulation at 10 and 75 Hz, that all diaphragm fiber types are susceptible to Neuromuscular Transmission failure, but that type IIb fibers are particularly susceptible at higher frequencies of stimulation.
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Neuromuscular Transmission failure during postnatal development.
Neuroscience Letters, 1991Co-Authors: Mario Fournier, Mahlet Alula, Gary C. SieckAbstract:Neuromuscular Transmission failure in rat diaphragm muscle was examined during the first two weeks of postnatal development, and was found to contribute significantly more to diaphragm fatigue induced by repetitive activation than in adult muscle. Intracellular analysis of evoked end-plate potentials indicated that Neuromuscular Transmission failure was due to both a block of action potential propagation and reduced synaptic efficacy.
Carlos B. Mantilla - One of the best experts on this subject based on the ideXlab platform.
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the novel trkb receptor agonist 7 8 dihydroxyflavone enhances Neuromuscular Transmission
Muscle & Nerve, 2012Co-Authors: Carlos B. Mantilla, Leonid G ErmilovAbstract:Neurotrophin signaling at the Neuromuscular junction modulates cholinergic Transmission and enhances Neuromuscular Transmission via the tropomyosin-related kinase receptor subtype B (TrkB).A novel flavonoid, 7,8-dihydroxyflavone (7,8-DHF), selectively activates TrkB receptors. Using TrkB(F616A) mice that are susceptible to specific inhibition of TrkB activity by 1NMPP1, we show that Neuromuscular Transmission is enhanced by 7,8-DHF (∽32%) via activation of TrkB in diaphragm muscle. The small molecule 7,8-DHF may constitute a novel therapy to improve Neuromuscular function.
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Neurotrophins improve Neuromuscular Transmission in the adult rat diaphragm.
Muscle & Nerve, 2004Co-Authors: Carlos B. Mantilla, W. Z. Zhan, Gary C. SieckAbstract:Neurotrophins modulate acute and sustained synaptic plasticity. In cultured Xenopus laevis Neuromuscular junctions, neurotrophins improve Neuromuscular Transmission. Whether this influence exists at the mammalian Neuromuscular junction is unknown. We hypothesized that neurotrophins improve Neuromuscular Transmission at Neuromuscular junctions of adult rat diaphragm muscle fibers. A diaphragm muscle-phrenic nerve preparation was used to determine the effects of brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4) and K252a [tyrosine kinase (Trk) receptor inhibitor] on the extent of Neuromuscular Transmission failure induced by repetitive nerve stimulation. We found significant enhancement of Neuromuscular Transmission with BDNF or NT-4 treatment, whereas K252a treatment worsened Neuromuscular Transmission. In contrast, diaphragm muscle contractile and fatigue properties were unaffected by neurotrophin or K252a treatment. These results demonstrate that BDNF and NT-4 improve synaptic Transmission in the adult rat diaphragm muscle, likely in a Trk-dependent fashion. Neurotrophins may constitute a novel therapeutic target to improve Neuromuscular function in the diaphragm.
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Regulation of Neuromuscular Transmission by neurotrophins.
Sheng li xue bao : [Acta physiologica Sinica], 2003Co-Authors: Wen Zhi Zhan, Carlos B. Mantilla, Gary C. SieckAbstract:Motor units comprise a motoneuron and the muscle fibers it innervates. Neuromuscular Transmission is tightly regulated to match the activity of individual motor units. Activity-dependent release of neuromodulators at the Neuromuscular junction (NMJ) determines the efficacy of Transmission. The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) are produced by motoneurons and muscle fibers, and their release by skeletal muscle is regulated by muscle activity. BDNF and NT-4 enhance both spontaneous and evoked synaptic Transmission at NMJs via activation of the tyrosine kinase receptor B (TrkB). Improvements in Neuromuscular Transmission may result from increased release of synaptic vesicles, either by presynaptic alterations in Ca(2+) transients or facilitated vesicular exocytosis. In fact, BDNF potentiates intracellular Ca(2+) release presynaptically and BDNF-induced TrkB activation also results in phosphorylation of synapsin I via mitogen activated protein kinase, which increases the number of synaptic vesicles available for release. Neurotrophins may also regulate synaptic Transmission at the NMJ by increasing local release of neuregulin or other nerve-derived modulators. We review recent studies on the regulation of Neuromuscular Transmission, the motor unit-specific properties of NMJs and the effects of neurotrophins on synaptic efficacy at the NMJ.
Ricardo A Maselli - One of the best experts on this subject based on the ideXlab platform.
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Presynaptic failure of Neuromuscular Transmission and synaptic remodeling in EA2
Neurology, 2003Co-Authors: Ricardo A Maselli, Vanessa Dunne, Michael C. Graves, Robert W Baloh, Robert L WollmannAbstract:Objective: To further investigate the basis of abnormal Neuromuscular Transmission in two patients with congenital myasthenic syndrome associated with episodic ataxia type 2 (EA2) using stimulated single fiber EMG (SFEMG) and in vitro microelectrode studies. Methods: Two patients with genetically characterized EA2 previously shown to have abnormal Neuromuscular Transmission by voluntary SFEMG were studied with stimulated SFEMG and anconeus muscle biopsy with microelectrode studies and electron microscopy of the Neuromuscular junction. Results: In vivo stimulated SFEMG showed signs of presynaptic failure, with jitter and blocking that improved with increased stimulation frequency. Additional evidence of presynaptic failure was provided by the in vitro microelectrode studies, which showed marked reduction of the end plate potential quantal content in both patients. Of note, the end plate potentials showed high sensitivity to N-type blockade with ω-conotoxin not seen in controls. The ultrastructural studies revealed some evidence of small nerve terminals apposed to normal or mildly overdeveloped postsynaptic membranes, suggesting an ongoing degenerative process. Conclusions: The authors demonstrated presynaptic failure of neuroTransmission in patients with heterozygous nonsense mutations in CACNA1A . The contribution of non-P-type calcium channels to the process of neurotransmitter release in these patients likely represents a compensatory mechanism, which is insufficient to restore normal Neuromuscular Transmission.
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Presynaptic failure of Neuromuscular Transmission and synaptic remodeling in EA2
Neurology, 2003Co-Authors: Ricardo A Maselli, Vanessa Dunne, Michael C. Graves, Robert W Baloh, Robert L WollmannAbstract:Objective: To further investigate the basis of abnormal Neuromuscular Transmission in two patients with congenital myasthenic syndrome associated with episodic ataxia type 2 (EA2) using stimulated single fiber EMG (SFEMG) and in vitro microelectrode studies. Methods: Two patients with genetically characterized EA2 previously shown to have abnormal Neuromuscular Transmission by voluntary SFEMG were studied with stimulated SFEMG and anconeus muscle biopsy with microelectrode studies and electron microscopy of the Neuromuscular junction. Results: In vivo stimulated SFEMG showed signs of presynaptic failure, with jitter and blocking that improved with increased stimulation frequency. Additional evidence of presynaptic failure was provided by the in vitro microelectrode studies, which showed marked reduction of the end plate potential quantal content in both patients. Of note, the end plate potentials showed high sensitivity to N-type blockade with ω-conotoxin not seen in controls. The ultrastructural studies revealed some evidence of small nerve terminals apposed to normal or mildly overdeveloped postsynaptic membranes, suggesting an ongoing degenerative process. Conclusions: The authors demonstrated presynaptic failure of neuroTransmission in patients with heterozygous nonsense mutations in CACNA1A . The contribution of non-P-type calcium channels to the process of neurotransmitter release in these patients likely represents a compensatory mechanism, which is insufficient to restore normal Neuromuscular Transmission.
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Neuromuscular Transmission as a function of motor unit size in patients with prior poliomyelitis.
Muscle & Nerve, 1992Co-Authors: Ricardo A Maselli, Neil R. Cashman, Robert Wollman, Edgar F. Salazar-grueso, Raymond P. RoosAbstract:We studied Neuromuscular Transmission in 16 patients with prior poliomyelitis by measuring single fiber electromyographic (SFEMG) jitter. This was compared with 3 indirect methods of assessing reinnervation: SFEMG fiber density, macro EMG, and the presence of fiber type grouping on muscle biopsy. In patients with acute poliomyelitis before the age of 10, there was a positive correlation between the extent of Neuromuscular Transmission impairment, demonstrated by increased SFEMG jitter, and the enlargement of the motor unit, as indicated by increased fiber density, increased macro EMG signals, and fiber type grouping on muscle biopsy. However, there was no correlation between any of these parameters and the presence or absence of new symptoms of weakness. These findings suggest that impaired Neuromuscular Transmission is most common in patients with prior poliomyelitis whose motor units have been maximally enlarged by axonal sprouting, but is independent of the presence or absence of new symptoms of weakness.
Andrew G. Engel - One of the best experts on this subject based on the ideXlab platform.
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impaired synaptic development maintenance and Neuromuscular Transmission in lrp4 related myasthenia
JAMA Neurology, 2015Co-Authors: Duygu Selcen, Bisei Ohkawara, Xin Ming Shen, Kathleen M Mcevoy, Kinji Ohno, Andrew G. EngelAbstract:Importance Congenital myasthenic syndromes (CMS) are heterogeneous disorders. Defining the phenotypic features, genetic basis, and pathomechanisms of a CMS is relevant to prognosis, genetic counseling, and therapy. Objectives To characterize clinical, structural, electrophysiologic, and genetic features of a CMS and to search for optimal therapy. Design, Settings, and Participants Two sisters with CMS affecting the limb-girdle muscles were investigated between 2012 and 2014 at an academic medical center by clinical observation, in vitro analysis of Neuromuscular Transmission, cytochemical and electron microscopy studies of the Neuromuscular junction, exome sequencing, expression studies in HEK293 and COS7 cells, and for response to therapy, and they were compared with 15 historical control participants. Main Outcomes and Measures We identified the disease gene and mutation, confirmed pathogenicity of the mutation by expression studies, and instituted optimal pharmacotherapy. Results Quantitative analysis of single EP regions was done for all 15 control participants and microelectrode studies of Neuromuscular Transmission and α-bgt binding sites per EP was conducted for 13 control participants. Examination of the older sister’s intercostal muscle end plates (EPs) showed them to be abnormally small, with attenuated reactivities for the acetylcholine receptor and acetylcholinesterase. Most EPs had poorly differentiated or degenerate junctional folds, and some appeared denuded of nerve terminals. The amplitude of the EP potential (EPP), the miniature EPP, and the quantal content of the EPP were all markedly reduced. Exome sequencing identified a novel homozygous p.Glu1233Ala mutation in low-density lipoprotein receptor–related protein 4 (LRP4), a coreceptor for agrin to activate muscle-specific tyrosine kinase (MuSK), which is required for EP development and maintenance. Expression studies indicate that the mutation compromises the ability of LRP4 to bind to, phosphorylate, and activate MuSK. Treatment with albuterol sulfate improved the patients’ symptoms. A previously identified patient harboring 2 heterozygous mutations in LRP4 had structurally abnormal intercostal EPs but no identifiable defect of Neuromuscular Transmission at these EPs. Conclusions and Relevance We identified a second CMS kinship harboring mutations inLRP4, identified the mechanisms that impair Neuromuscular Transmission, and mitigated the disease by appropriate therapy.
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Effects of the quinoline derivatives quinine, quinidine, and chloroquine on Neuromuscular Transmission.
Brain Research, 1996Co-Authors: Jörn P. Sieb, Margherita Milone, Andrew G. EngelAbstract:The quinoline derivatives quinine, its stereoisomer quinidine, and chloroquine may worsen or provoke disorders of Neuromuscular Transmission. In this study, we investigate effects of these drugs on Neuromuscular Transmission by conventional microelectrode as well as patch-clamp techniques. At 5 x 10(-5) M, quinine, quinidine, and chloroquine reduced the quantal content of the end-plate potential by 37-45%. Between 10(-6) and 10(-4) M, all 3 drugs progressively decreased the amplitude and decay time constant of miniature end-plate potential (MEPP) and miniature end-plate current (MEPC); at 5 x 10(-3) M, the MEPP became undetectable. The effect on the MEPP was not reversed by 1 microgram/mL neostigmine. Single-channel patch-clamp analysis of the effects of quinine showed that this agent causes a long-lived open-channel as well as a closed-channel block of AChR. Tests for competitive inhibition or desensitization of the acetylcholine receptor (AChR) by quinine in concentrations that had a marked effect on the MEPC and on single-channel open and closed intervals were negative. Because quinoline drugs adversely affect both presynaptic and postsynaptic aspects of Neuromuscular Transmission at concentrations close to those employed in clinical practice, they should not be used, or used with caution, in disorders that compromise the safety margin of Neuromuscular Transmission.
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Ephedrine: effects on Neuromuscular Transmission
Brain Research, 1993Co-Authors: Jo¨rn P. Sieb, Andrew G. EngelAbstract:(−)-Ephedrine has been used in the treatment of patients with myasthenia gravis. To investigate the possible effects of ephedrine on Neuromuscular Transmission, canine intercostal muscle endplates were studied by microelectrode techniques. At concentrations less than 10−4 M, ephedrine had no effect on Neuromuscular Transmission. At a concentration of 10−4 M, ephedrine increased the quantal content of the endplate potential by 21%. The presynaptic store of acetylcholine quanta available for immediate release was unchanged, but the probability of quantal release was increased by 16%. At this concentration, ephedrine decreased the amplitude of the miniature endplate potential by 38%. In the presence of 10−3 M ephedrine, the miniature endplate potentials and currents became undetectable. The kinetic properties of the acetylcholine receptor channel were studied by analysis of acetylcholine-induced endplate current noise. At 10−4 M, ephedrine reduced the channel conductance by 43% but had no effect on the open time. At 5×10−4 M, ephedrine reduced the channel conductance by 84% and increased the open time by 23 percent.
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Neuromuscular Transmission in the mdx mouse
Muscle & Nerve, 1990Co-Authors: Alexandre Nagel, Frank Lehmann-horn, Andrew G. EngelAbstract:The mdx mouse is an animal model for human Duchenne dystrophy. In both disorders, the muscle fiber plasma membrane is rendered selectively vulnerable by dystrophin deficiency. In both disorders there are also ultrastructural abnormalities involving the postsynaptic membrane of the Neuromuscular junction. The object of this electrophysiologic study was to determine whether the observed ultrastructural abnormalities at the mdx Neuromuscular junction are associated with an abnormality of Neuromuscular Transmission. In comparison with age-matched control mice, the mdx mice show an abnormal, age-dependent decrease of the amplitude of the miniature end-plate potential and aconcomitant increase in the quantal content of the end-plate potential. Consequently, the safety margin of Neuromuscular Transmission is not impaired.
Robert L Wollmann - One of the best experts on this subject based on the ideXlab platform.
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Presynaptic failure of Neuromuscular Transmission and synaptic remodeling in EA2
Neurology, 2003Co-Authors: Ricardo A Maselli, Vanessa Dunne, Michael C. Graves, Robert W Baloh, Robert L WollmannAbstract:Objective: To further investigate the basis of abnormal Neuromuscular Transmission in two patients with congenital myasthenic syndrome associated with episodic ataxia type 2 (EA2) using stimulated single fiber EMG (SFEMG) and in vitro microelectrode studies. Methods: Two patients with genetically characterized EA2 previously shown to have abnormal Neuromuscular Transmission by voluntary SFEMG were studied with stimulated SFEMG and anconeus muscle biopsy with microelectrode studies and electron microscopy of the Neuromuscular junction. Results: In vivo stimulated SFEMG showed signs of presynaptic failure, with jitter and blocking that improved with increased stimulation frequency. Additional evidence of presynaptic failure was provided by the in vitro microelectrode studies, which showed marked reduction of the end plate potential quantal content in both patients. Of note, the end plate potentials showed high sensitivity to N-type blockade with ω-conotoxin not seen in controls. The ultrastructural studies revealed some evidence of small nerve terminals apposed to normal or mildly overdeveloped postsynaptic membranes, suggesting an ongoing degenerative process. Conclusions: The authors demonstrated presynaptic failure of neuroTransmission in patients with heterozygous nonsense mutations in CACNA1A . The contribution of non-P-type calcium channels to the process of neurotransmitter release in these patients likely represents a compensatory mechanism, which is insufficient to restore normal Neuromuscular Transmission.
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Presynaptic failure of Neuromuscular Transmission and synaptic remodeling in EA2
Neurology, 2003Co-Authors: Ricardo A Maselli, Vanessa Dunne, Michael C. Graves, Robert W Baloh, Robert L WollmannAbstract:Objective: To further investigate the basis of abnormal Neuromuscular Transmission in two patients with congenital myasthenic syndrome associated with episodic ataxia type 2 (EA2) using stimulated single fiber EMG (SFEMG) and in vitro microelectrode studies. Methods: Two patients with genetically characterized EA2 previously shown to have abnormal Neuromuscular Transmission by voluntary SFEMG were studied with stimulated SFEMG and anconeus muscle biopsy with microelectrode studies and electron microscopy of the Neuromuscular junction. Results: In vivo stimulated SFEMG showed signs of presynaptic failure, with jitter and blocking that improved with increased stimulation frequency. Additional evidence of presynaptic failure was provided by the in vitro microelectrode studies, which showed marked reduction of the end plate potential quantal content in both patients. Of note, the end plate potentials showed high sensitivity to N-type blockade with ω-conotoxin not seen in controls. The ultrastructural studies revealed some evidence of small nerve terminals apposed to normal or mildly overdeveloped postsynaptic membranes, suggesting an ongoing degenerative process. Conclusions: The authors demonstrated presynaptic failure of neuroTransmission in patients with heterozygous nonsense mutations in CACNA1A . The contribution of non-P-type calcium channels to the process of neurotransmitter release in these patients likely represents a compensatory mechanism, which is insufficient to restore normal Neuromuscular Transmission.
