Neuromuscular reinnervation efficacy using a YFP model

Woollard, Alexander; Lichtman, Jeff W.; Rolfe, KJ; Grobbelaar, Adriaan O.

doi:10.1016/j.bjps.2020.10.004

Cited by 1 publication

(3 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We analyzed the long-term morphological alterations associated with irreversible denervation of the cranial LAL muscle. Besides its usefulness to study the specific clinical consequences associated with the denervation of head/neck muscles [ 24 ], the LAL muscle offers several experimental advantages, as it is a superficially exposed, flat, and thin cranial muscle, allowing repeated in vivo manipulation and microscopic observation of NMJs in whole-mount preparations [ 23 , 25 , 26 ]. We have recently refined a muscle denervation procedure to specifically target muscles from the cranial region, by resecting a 5-mm segment of the right posterior auricular nerve branch (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Possible explanations are the longer distances that regenerating human motor axons must travel in comparison to rodents ones, along with the similar (or even slower) axonal growth rate observed in humans compared to rodents [ 33 ]. Moreover, although significant advances have been made in microsurgical techniques used for facial nerve repair, the recovery of motor function has shown results varying from excellent to sub-optimal, being fair-to-good results higher in proportion [ 9 , 24 ]. Interestingly, studies using different paradigms of peripheral nerve damage have shown that morphological regeneration of the NMJ does not necessarily correlate with motor function recovery [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we have conducted a detailed characterization of the long-term consequences of NMJ short-term reinnervation (i.e., after partial denervation) and compared it to those occurring after irreversible (chronic) denervation. We have employed the cranial levator auris longus (LAL) muscle due to its high accessibility for morphometric and functional analyses [ 23 ], its suitability for short-term reinnervation [ 23 ], and its potential clinical relevance regarding the poor recovery outcomes observed in head muscles [ 24 ]. Our findings show that fragmentation and poly-innervation of the NMJ postsynaptic domain remain long after re-innervation and synaptic transmission recovered.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Functional regeneration of the murine neuromuscular synapse relies on long-lasting morphological adaptations

et al. 2022

View full text Add to dashboard Cite

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.

show abstract