scholarly journals Effect of salbutamol on neuromuscular junction function and structure in a mouse model of DOK7 congenital myasthenia

2020 ◽  
Vol 29 (14) ◽  
pp. 2325-2336 ◽  
Author(s):  
Richard G Webster ◽  
An E Vanhaesebrouck ◽  
Susan E Maxwell ◽  
Judith A Cossins ◽  
Weiwei Liu ◽  
...  
Keyword(s):  
Weight Gain ◽  
Neuromuscular Junction ◽  
Mouse Model ◽  
Structural Integrity ◽  
Ex Vivo ◽  
Adrenergic Agonists ◽  
Mice Model ◽  
Synaptic Structure ◽  
Perinatal Lethality ◽  
And Function

Abstract Congenital myasthenic syndromes (CMS) are characterized by fatigable muscle weakness resulting from impaired neuromuscular transmission. β2-adrenergic agonists are an effective treatment for DOK7-CMS. DOK7 is a component within the AGRN-LRP4-MUSK-DOK7 signalling pathway that is key for the formation and maintenance of the synaptic structure of the neuromuscular junction (NMJ). The precise mechanism of action of β2-adrenergic agonists at the NMJ is not fully understood. In this study, we investigated whether β2-adrenergic agonists improve both neurotransmission and structural integrity of the NMJ in a mouse model of DOK7-CMS. Ex-vivo electrophysiological techniques and microscopy of the NMJ were used to study the effect of salbutamol, a β2-adrenergic agonist, on synaptic structure and function. DOK7-CMS model mice displayed a severe phenotype with reduced weight gain and perinatal lethality. Salbutamol treatment improved weight gain and survival in DOK7 myasthenic mice. Model animals had fewer active NMJs, detectable by endplate recordings, compared with age-matched wild-type littermates. Salbutamol treatment increased the number of detectable NMJs during endplate recording. Correspondingly, model mice had fewer acetylcholine receptor-stained NMJs detected by fluorescent labelling, but following salbutamol treatment an increased number were detectable. The data demonstrate that salbutamol can prolong survival and increase NMJ number in a severe model of DOK7-CMS.

scholarly journals Neurexin–Neuroligin 1 regulates synaptic morphology and functions via the WAVE regulatory complex in Drosophila neuromuscular junction

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Guanglin Xing ◽  
Moyi Li ◽  
Yichen Sun ◽  
Menglong Rui ◽  
Yan Zhuang ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Molecular Mechanisms ◽  
Postsynaptic Membrane ◽  
Synaptic Function ◽  
Actin Assembly ◽  
Actin Reorganization ◽  
Synaptic Structure ◽  
Structural And Functional Properties ◽  
Regulatory Complex ◽  
And Function

Neuroligins are postsynaptic adhesion molecules that are essential for postsynaptic specialization and synaptic function. But the underlying molecular mechanisms of neuroligin functions remain unclear. We found that Drosophila Neuroligin 1 (DNlg1) regulates synaptic structure and function through WAVE regulatory complex (WRC)-mediated postsynaptic actin reorganization. The disruption of DNlg1, DNlg2, or their presynaptic partner neurexin (DNrx) led to a dramatic decrease in the amount of F-actin. Further study showed that DNlg1, but not DNlg2 or DNlg3, directly interacts with the WRC via its C-terminal interacting receptor sequence. That interaction is required to recruit WRC to the postsynaptic membrane to promote F-actin assembly. Furthermore, the interaction between DNlg1 and the WRC is essential for DNlg1 to rescue the morphological and electrophysiological defects in dnlg1 mutants. Our results reveal a novel mechanism by which the DNrx-DNlg1 trans-synaptic interaction coordinates structural and functional properties at the neuromuscular junction.

scholarly journals The Neuromuscular Junction in Health and Disease: Molecular Mechanisms Governing Synaptic Formation and Homeostasis

2020 ◽  
Vol 13 ◽  
Author(s):  
Pedro M. Rodríguez Cruz ◽  
Judith Cossins ◽  
David Beeson ◽  
Angela Vincent
Keyword(s):  
Neuromuscular Junction ◽  
Action Potential ◽  
Motor Neuron ◽  
Muscle Fiber ◽  
Neuromuscular Transmission ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Motor Nerve ◽  
And Function

The neuromuscular junction (NMJ) is a highly specialized synapse between a motor neuron nerve terminal and its muscle fiber that are responsible for converting electrical impulses generated by the motor neuron into electrical activity in the muscle fibers. On arrival of the motor nerve action potential, calcium enters the presynaptic terminal, which leads to the release of the neurotransmitter acetylcholine (ACh). ACh crosses the synaptic gap and binds to ACh receptors (AChRs) tightly clustered on the surface of the muscle fiber; this leads to the endplate potential which initiates the muscle action potential that results in muscle contraction. This is a simplified version of the events in neuromuscular transmission that take place within milliseconds, and are dependent on a tiny but highly structured NMJ. Much of this review is devoted to describing in more detail the development, maturation, maintenance and regeneration of the NMJ, but first we describe briefly the most important molecules involved and the conditions that affect their numbers and function. Most important clinically worldwide, are myasthenia gravis (MG), the Lambert-Eaton myasthenic syndrome (LEMS) and congenital myasthenic syndromes (CMS), each of which causes specific molecular defects. In addition, we mention the neurotoxins from bacteria, snakes and many other species that interfere with neuromuscular transmission and cause potentially fatal diseases, but have also provided useful probes for investigating neuromuscular transmission. There are also changes in NMJ structure and function in motor neuron disease, spinal muscle atrophy and sarcopenia that are likely to be secondary but might provide treatment targets. The NMJ is one of the best studied and most disease-prone synapses in the nervous system and it is amenable to in vivo and ex vivo investigation and to systemic therapies that can help restore normal function.

scholarly journals The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction

Cell Reports ◽  
2021 ◽  
Vol 34 (7) ◽  
pp. 108753 ◽  
Author(s):  
Helen M. Belalcazar ◽  
Emily L. Hendricks ◽  
Sumaira Zamurrad ◽  
Faith L.W. Liebl ◽  
Julie Secombe
Keyword(s):  
Neuromuscular Junction ◽  
Structure And Function ◽  
Histone Demethylase ◽  
Synaptic Structure ◽  
And Function

scholarly journals APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Hong Y Choi ◽  
Yun Liu ◽  
Christian Tennert ◽  
Yoshie Sugiura ◽  
Andromachi Karakatsani ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Transmembrane Domain ◽  
Neuromuscular Synapse ◽  
Apoe Receptor ◽  
Cultured Myotubes ◽  
Perinatal Lethality ◽  
And Function ◽  
Achr Clustering

ApoE, ApoE receptors and APP cooperate in the pathogenesis of Alzheimer’s disease. Intriguingly, the ApoE receptor LRP4 and APP are also required for normal formation and function of the neuromuscular junction (NMJ). In this study, we show that APP interacts with LRP4, an obligate co-receptor for muscle-specific tyrosine kinase (MuSK). Agrin, a ligand for LRP4, also binds to APP and co-operatively enhances the interaction of APP with LRP4. In cultured myotubes, APP synergistically increases agrin-induced acetylcholine receptor (AChR) clustering. Deletion of the transmembrane domain of LRP4 (LRP4 ECD) results in growth retardation of the NMJ, and these defects are markedly enhanced in APP−/−;LRP4ECD/ECD mice. Double mutant NMJs are significantly reduced in size and number, resulting in perinatal lethality. Our findings reveal novel roles for APP in regulating neuromuscular synapse formation through hetero-oligomeric interaction with LRP4 and agrin and thereby provide new insights into the molecular mechanisms that govern NMJ formation and maintenance.

scholarly journals Glial Cells Maintain Synaptic Structure and Function and Promote Development of the Neuromuscular Junction In Vivo

Neuron ◽  
2003 ◽  
Vol 40 (3) ◽  
pp. 563-580 ◽  
Author(s):  
Linga V. Reddy ◽  
Samir Koirala ◽  
Yoshie Sugiura ◽  
Albert A. Herrera ◽  
Chien-Ping Ko
Keyword(s):  
Neuromuscular Junction ◽  
Glial Cells ◽  
Structure And Function ◽  
Synaptic Structure ◽  
And Function

scholarly journals Islet Transplantation in the Lung via Endoscopic Aerosolization: Investigation of Feasibility, Islet Cluster Cell Vitality, and Structural Integrity

2020 ◽  
Vol 29 ◽  
pp. 096368972094924
Author(s):  
Hien Lau ◽  
Tanja Khosrawipour ◽  
Michael Alexander ◽  
Shiri Li ◽  
Agata Mikolajczyk ◽  
...  
Keyword(s):  
Islet Transplantation ◽  
Islet Cell ◽  
Structural Integrity ◽  
Ex Vivo ◽  
Swine Model ◽  
Cell Clusters ◽  
Cell Vitality ◽  
Promising Tool ◽  
Significant Difference ◽  
And Function

Aerosolized drug delivery has recently attracted much attention as a possible new tool for the delivery of complex nanoparticles. This study aims to investigate whether catheter-based aerosolization of islets via endobronchial systems is a feasible option in islet transplantation. Besides investigating the feasibility of islet aerosolization, we also examined cluster cell vitality and structural integrity of the islets following aerosolization. Using an ex vivo postmortem swine model, porcine pancreatic islets were isolated and aerosolized with an endoscopic spray catheter. Following aerosolization, islet cell vitality and function were assessed via Calcein AM and propidium iodide as well as insulin production after glucose exposure. In the final step, the overall feasibility of the procedure and structural integrity of cells were analyzed and evaluated with respect to clinical applicability. No significant difference was detected in the viability of control islets (90.67 ± 2.19) vs aerosolized islets (90.68 ± 1.20). Similarly, there was no significant difference in control islets (1.62 ± 0.086) vs aerosolized islets (1.42 ± 0.11) regarding insulin release after stimulation. Indocyanine green marked islets were transplanted into the lung without major difficulty. Histological analysis confirmed retained structural integrity and predominant location in the alveolar cavity. Our ex vivo data suggest that catheter-based aerosolized islet cell delivery is a promising tool for the application of cell clusters. According to our data, islet cell clusters delivery is feasible from a mechanical and physical perspective. Moreover, cell vitality and structural integrity remain largely unaffected following aerosolization. These preliminary results are encouraging and represent a first step toward endoscopically assisted islet cell implantation in the lung.

scholarly journals The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction

2020 ◽  
Author(s):  
Helen M. Belalcazar ◽  
Emily L. Hendricks ◽  
Sumaira Zamurrad ◽  
Faith L.W. Liebl ◽  
Julie Secombe
Keyword(s):  
Neuromuscular Junction ◽  
Histone Demethylase ◽  
Synaptic Function ◽  
Complex Nature ◽  
Synaptic Structure ◽  
Genes Encoding ◽  
Demethylase Activity ◽  
Larval Neuromuscular Junction ◽  
And Function ◽  
Structure And Activity

SummaryMutations in the genes encoding the KDM5 family of histone demethylases are observed in individuals with intellectual disability (ID). Despite clear evidence linking KDM5 function to neurodevelopmental pathways, how this family of proteins impacts transcriptional programs to mediate synaptic structure and activity remains unclear. Using the Drosophila larval neuromuscular junction (NMJ), we show that KDM5 is required for neuroanatomical development and synaptic function. The JmjC-domain encoded histone demethylase activity of KDM5, which is expected to be diminished by many ID-associated alleles and required for appropriate synaptic morphology and neurotransmission. The C5HC2 zinc finger of KDM5 is also involved, as an ID-associated mutation in this motif reduces NMJ bouton number but increases bouton size. KDM5 therefore uses demethylase-dependent and independent mechanisms to regulate NMJ structure and activity, highlighting the complex nature by which this chromatin modifier carries out its neuronal gene regulatory programs.

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