Functional regeneration of the murine neuromuscular synapse relies on long-lasting morphological adaptations
Abstract Background In a broad variety of species, muscle contraction is controlled at the neuromuscular junction (NMJ), the peripheral synapse composed of a motor nerve terminal, a muscle specialization, and non-myelinating terminal Schwann cells. While peripheral nerve damage leads to successful N...
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| Format: | Article |
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BMC
2022-07-01
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| Series: | BMC Biology |
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| Online Access: | https://doi.org/10.1186/s12915-022-01358-4 |
| _version_ | 1811219121649483776 |
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| author | Francisca Bermedo-García Diego Zelada Esperanza Martínez Lucía Tabares Juan Pablo Henríquez |
| author_facet | Francisca Bermedo-García Diego Zelada Esperanza Martínez Lucía Tabares Juan Pablo Henríquez |
| author_sort | Francisca Bermedo-García |
| collection | DOAJ |
| description | Abstract Background In a broad variety of species, muscle contraction is controlled at the neuromuscular junction (NMJ), the peripheral synapse composed of a motor nerve terminal, a muscle specialization, and non-myelinating terminal Schwann cells. While peripheral nerve damage leads to successful NMJ reinnervation in animal models, muscle fiber reinnervation in human patients is largely inefficient. Interestingly, some hallmarks of NMJ denervation and early reinnervation in murine species, such as fragmentation and poly-innervation, are also phenotypes of aged NMJs or even of unaltered conditions in other species, including humans. We have reasoned that rather than features of NMJ decline, such cellular responses could represent synaptic adaptations to accomplish proper functional recovery. Here, we have experimentally tackled this idea through a detailed comparative study of the short- and long-term consequences of irreversible (chronic) and reversible (partial) NMJ denervation in the convenient cranial levator auris longus muscle. Results Our findings reveal that irreversible muscle denervation results in highly fragmented postsynaptic domains and marked ectopic acetylcholine receptor clustering along with significant terminal Schwann cells sprouting and progressive detachment from the NMJ. Remarkably, even though reversible nerve damage led to complete reinnervation after 11 days, we found that more than 30% of NMJs are poly-innervated and around 65% of postsynaptic domains are fragmented even 3 months after injury, whereas synaptic transmission is fully recovered two months after nerve injury. While postsynaptic stability was irreversibly decreased after chronic denervation, this parameter was only transiently affected by partial NMJ denervation. In addition, we found that a combination of morphometric analyses and postsynaptic stability determinations allows discriminating two distinct forms of NMJ fragmentation, stable-smooth and unstable-blurred, which correlate with their regeneration potential. Conclusions Together, our data unveil that reversible nerve damage imprints a long-lasting reminiscence in the NMJ that results in the rearrangement of its cellular components. Instead of being predictive of NMJ decline, these traits may represent an efficient adaptive response for proper functional recovery. As such, these features are relevant targets to be considered in strategies aimed to restore motor function in detrimental conditions for peripheral innervation. |
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| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1741-7007 |
| language | English |
| last_indexed | 2024-04-12T07:21:06Z |
| publishDate | 2022-07-01 |
| publisher | BMC |
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| series | BMC Biology |
| spelling | doaj.art-fd675740d6234605aebb58ddbe690c202022-12-22T03:42:20ZengBMCBMC Biology1741-70072022-07-0120111810.1186/s12915-022-01358-4Functional regeneration of the murine neuromuscular synapse relies on long-lasting morphological adaptationsFrancisca Bermedo-García0Diego Zelada1Esperanza Martínez2Lucía Tabares3Juan Pablo Henríquez4Laboratory of Neuromuscular Studies (NeSt Lab), Group for the Study of Developmental Processes (GDeP), Department of Cell Biology, Faculty of Biological Sciences, Universidad de ConcepciónLaboratory of Neuromuscular Studies (NeSt Lab), Group for the Study of Developmental Processes (GDeP), Department of Cell Biology, Faculty of Biological Sciences, Universidad de ConcepciónLaboratory of Neuromuscular Studies (NeSt Lab), Group for the Study of Developmental Processes (GDeP), Department of Cell Biology, Faculty of Biological Sciences, Universidad de ConcepciónDepartment of Medical Physiology and Biophysics, School of Medicine, Universidad de SevillaLaboratory of Neuromuscular Studies (NeSt Lab), Group for the Study of Developmental Processes (GDeP), Department of Cell Biology, Faculty of Biological Sciences, Universidad de ConcepciónAbstract Background In a broad variety of species, muscle contraction is controlled at the neuromuscular junction (NMJ), the peripheral synapse composed of a motor nerve terminal, a muscle specialization, and non-myelinating terminal Schwann cells. While peripheral nerve damage leads to successful NMJ reinnervation in animal models, muscle fiber reinnervation in human patients is largely inefficient. Interestingly, some hallmarks of NMJ denervation and early reinnervation in murine species, such as fragmentation and poly-innervation, are also phenotypes of aged NMJs or even of unaltered conditions in other species, including humans. We have reasoned that rather than features of NMJ decline, such cellular responses could represent synaptic adaptations to accomplish proper functional recovery. Here, we have experimentally tackled this idea through a detailed comparative study of the short- and long-term consequences of irreversible (chronic) and reversible (partial) NMJ denervation in the convenient cranial levator auris longus muscle. Results Our findings reveal that irreversible muscle denervation results in highly fragmented postsynaptic domains and marked ectopic acetylcholine receptor clustering along with significant terminal Schwann cells sprouting and progressive detachment from the NMJ. Remarkably, even though reversible nerve damage led to complete reinnervation after 11 days, we found that more than 30% of NMJs are poly-innervated and around 65% of postsynaptic domains are fragmented even 3 months after injury, whereas synaptic transmission is fully recovered two months after nerve injury. While postsynaptic stability was irreversibly decreased after chronic denervation, this parameter was only transiently affected by partial NMJ denervation. In addition, we found that a combination of morphometric analyses and postsynaptic stability determinations allows discriminating two distinct forms of NMJ fragmentation, stable-smooth and unstable-blurred, which correlate with their regeneration potential. Conclusions Together, our data unveil that reversible nerve damage imprints a long-lasting reminiscence in the NMJ that results in the rearrangement of its cellular components. Instead of being predictive of NMJ decline, these traits may represent an efficient adaptive response for proper functional recovery. As such, these features are relevant targets to be considered in strategies aimed to restore motor function in detrimental conditions for peripheral innervation.https://doi.org/10.1186/s12915-022-01358-4Neuromuscular junctionPresynapticPostsynapticDenervationRegenerationFragmentation |
| spellingShingle | Francisca Bermedo-García Diego Zelada Esperanza Martínez Lucía Tabares Juan Pablo Henríquez Functional regeneration of the murine neuromuscular synapse relies on long-lasting morphological adaptations BMC Biology Neuromuscular junction Presynaptic Postsynaptic Denervation Regeneration Fragmentation |
| title | Functional regeneration of the murine neuromuscular synapse relies on long-lasting morphological adaptations |
| title_full | Functional regeneration of the murine neuromuscular synapse relies on long-lasting morphological adaptations |
| title_fullStr | Functional regeneration of the murine neuromuscular synapse relies on long-lasting morphological adaptations |
| title_full_unstemmed | Functional regeneration of the murine neuromuscular synapse relies on long-lasting morphological adaptations |
| title_short | Functional regeneration of the murine neuromuscular synapse relies on long-lasting morphological adaptations |
| title_sort | functional regeneration of the murine neuromuscular synapse relies on long lasting morphological adaptations |
| topic | Neuromuscular junction Presynaptic Postsynaptic Denervation Regeneration Fragmentation |
| url | https://doi.org/10.1186/s12915-022-01358-4 |
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