The p75NTR neurotrophin receptor is required to organize the mature neuromuscular synapse by regulating synaptic vesicle availability

Acta Neuropathologica Communications

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[1] 0000 0000 8912 4050, grid.412185.b, Laboratory of Neural Plasticity, Center for Neurobiology and Integrative Physiology, Faculty of Sciences, Institute of Physiology, Universidad de Valparaíso, Valparaíso, Chile;0000 0000 8912 4050, grid.412185.b, Laboratory of Neural Plasticity, Center for Neurobiology and Integrative Physiology, Faculty of Sciences, Institute of Physiology, Universidad de Valparaíso, Valparaíso, Chile;grid.441845.8, Present Address: Health Sciences School, Universidad de Viña del Mar, Viña del Mar, Chile;0000 0001 2156 804X, grid.412848.3, Laboratory of Muscle Pathologies, Fragility and Aging, Department of Biological Sciences, Faculty of Life Sciences, Millennium Institute on Immunology and Immunotherapy, Universidad Andrés Bello, Santiago, Chile;0000 0001 2157 0406, grid.7870.8, Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile;0000 0001 2157 0406, grid.7870.8, Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile;0000 0001 2156 804X, grid.412848.3, Center for Aging and Regeneration (CARE), Institute of Biomedical Sciences (ICB), Faculty of Medicine and Faculty of Life Sciences, Universidad Andrés Bello, Santiago, Chile;0000 0001 2298 9663, grid.5380.e, Neuromuscular Studies Laboratory (NeSt Lab), Department of Cell Biology, Center for Advanced Microscopy (CMA BioBio), Universidad de Concepción, Concepción, Chile;0000 0004 0385 4466, grid.443909.3, Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile;Center for Geroscience, Brain Health and Metabolism, Santiago, Chile;0000 0004 0385 4466, grid.443909.3, Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile;0000 0004 0385 4466, grid.443909.3, Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile;Center for Geroscience, Brain Health and Metabolism, Santiago, Chile;0000 0004 0385 4466, grid.443909.3, Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile;0000 0000 8687 5377, grid.272799.0, Buck Institute for Research on Aging, 94945, Novato, CA, USA;0000 0004 0487 8785, grid.412199.6, Center for Integrative Biology, Faculty of Sciences, Universidad Mayor; FONDAP Center for Geroscience, Brain Health and Metabolism, Santiago, Chile;grid.10999.38, Department of Biomedical Sciences, Faculty of Health Sciences, Universidad de Talca, Talca, Chile;

关键词: Neuromuscular junction;    p75;    Neurotrophin;    Motor neuron;    Synaptic vesicles;   

DOI  :  10.1186/s40478-019-0802-7

来源: publisher

【 摘 要 】

The coordinated movement of organisms relies on efficient nerve-muscle communication at the neuromuscular junction. After peripheral nerve injury or neurodegeneration, motor neurons and Schwann cells increase the expression of the p75NTR pan-neurotrophin receptor. Even though p75NTR targeting has emerged as a promising therapeutic strategy to delay peripheral neuronal damage progression, the effects of long-term p75NTR inhibition at the mature neuromuscular junction have not been elucidated. We performed quantitative neuroanathomical analyses of the neuromuscular junction in p75NTR null mice by laser confocal and electron microscopy, which were complemented with electromyography, locomotor tests, and pharmacological intervention studies. Mature neuromuscular synapses of p75NTR null mice show impaired postsynaptic organization and ultrastructural complexity, which correlate with altered synaptic function at the levels of nerve activity-induced muscle responses, muscle fiber structure, force production, and locomotor performance. Our results on primary myotubes and denervated muscles indicate that muscle-derived p75NTR does not play a major role on postsynaptic organization. In turn, motor axon terminals of p75NTR null mice display a strong reduction in the number of synaptic vesicles and active zones. According to the observed pre and postsynaptic defects, pharmacological acetylcholinesterase inhibition rescued nerve-dependent muscle response and force production in p75NTR null mice. Our findings revealing that p75NTR is required to organize mature neuromuscular junctions contribute to a comprehensive view of the possible effects caused by therapeutic attempts to target p75NTR.

【 授权许可】

CC BY