Competition at silent synapses in reinnervated skeletal muscle

Abstract

Synaptic connections are made and broken in an activity-dependent manner in diverse regions of the nervous system. However, whether activity is strictly necessary for synapse elimination has not been resolved directly. Here we report that synaptic terminals occupying motor endplates made electrically silent by tetrodotoxin and alpha-bungarotoxin block were frequently displaced by regenerating axons that were also both inactive and synaptically ineffective. Thus, neither evoked nor spontaneous activation of acetylcholine receptors is required for competitive reoccupation of neuromuscular synaptic sites by regenerating motor axons.

Reinnervation of the tibialis anterior following sciatic nerve crush injury: A confocal microscopic study in transgenic mice

“…Previous work on tibial nerve crush injury suggests that although motor endplates may be transiently hyperinnervated, they are not hyperfunctional (Gillingwater, et al, 2004). Synaptic activity is not a prerequisite for motor endplate reinnervation following sciatic nerve injury (Costanzo, et al, 2000). However, in the setting of hyperinnervation, synaptic activity has been shown to contribute to the outcome of competition between axons (Buffelli, et al, 2003).…”

“…A. Confocal imaging of the tibialis anterior shows that motor endplates are singly innervated by terminal axons in uninjured adult mice. Axons are constitutively labeled with YFP in thy1-YFP (16) mice, while Alexa 594-bungarotoxin labeled acetylcholine receptors delineate motor endplates. B One week after sciatic nerve crush, all motor endplates are denervated, but YFP persists during the process of Wallerian degeneration.…”

“…Adult thy1-YFP (16) mice are characterized by 1:1 relationships between terminal axons and motor endplates. Following sciatic nerve crush injury, this relationship becomes dynamic, as imaged nerve terminals are completely denervated after one week following injury, partially reinnervated at two weeks, hyperinnervated at three and four weeks, and return to a 1:1 terminal axon to motor endplate ratio by six weeks, as noted in Table 1.…”

“…We utilize the thy1-YFP (16) line that constitutively expresses yellow fluorescent protein (YFP) in nearly all axons in order to evaluate temporal patterns of motor endplate reinnervation and axonal branching following nerve injury (Feng, et al, 2000). We have also bred thy1-CFP (23) mice whose axons constitutively express cyan fluorescent protein (CFP) to S100-GFP mice whose mature, differentiated Schwann cells (SCs) robustly express green fluorescent protein (GFP), and whose denervated and immature SCs have diminished or absent fluorescence (Jessen andMirsky, 2005, Zuo, et al, 2004).…”

Identity, developmental restriction and reactivity of extralaminar cells capping mammalian neuromuscular junctions

“…Degeneration of motor nerve terminals occurs rapidly after axon injury, axonal transport block or neuromuscular paralysis (Miledi and Slater, 1970;Brown et al, 1980;Hudson et al, 1984) and in early stages of motor neuron diseases, such as amyotrophic lateral sclerosis (ALS) (Fischer et al, 2004;Pun et al, 2006;David et al, 2007). Compensatory responses to such denervation include sprouting from intact neighbouring axons and regeneration of damaged axons (Brown and Ironton, 1978;Barry and Ribchester, 1995;Costanzo et al, 1999;Costanzo et al, 2000;Schaefer et al, 2005). Understanding the cellular organisation of NMJs and the mediators of their plasticity is therefore important: not only for the insights it provides into fundamental cell biology but also for identifying suitable cellular and molecular targets for effective treatment for ALS and other neuromuscular diseases.…”