Abstract
Schwann cells are integral components of vertebrate neuromuscular synapses; in their absence, pre-synaptic nerve terminals withdraw from post-synaptic muscles, leading to muscle denervation and synapse loss at the developing neuromuscular junction (NMJ). Here, we report a rescue of muscle denervation and neuromuscular synapses loss in type III Neuregulin 1 mutant mice (CRD-Nrg1−/−), which lack Schwann cells. We found that muscle denervation and neuromuscular synapse loss were prevented in CRD-Nrg1−/−mice when presynaptic activity was blocked by ablating a specific gene, such as Snap25 (synaptosomal-associated 25 kDa protein) or Chat (choline acetyltransferase). Further, these effects were mediated by a pathway that requires postsynaptic acetylcholine receptors (AChRs), because ablating Chrna1 (acetylcholine receptor α1 subunit), which encodes muscle-specific AChRs in CRD-Nrg1−/−mice also rescued muscle denervation. Moreover, genetically ablating muscle dihydropyridine receptor (DHPR) β1 subunit (Cacnb1) or ryanodine receptor 1 (Ryr1) also rescued muscle denervation and neuromuscular synapse loss in CRD-Nrg1−/−mice. Thus, these genetic manipulations follow a pathway–from presynaptic to postsynaptic, and, ultimately to muscle activity mediated by DHPRs and Ryr1. Importantly, electrophysiological analyses reveal robust synaptic activity in the rescued, Schwann-cell deficient NMJs in CRD-Nrg1−/−Cacnb1−/−or CRD-Nrg1−/−Ryr1−/−mutant mice. Thus, a blockade of synaptic activity, although sufficient, is not necessary to preserve NMJs that lack Schwann cells. Instead, a blockade of muscle activity mediated by DHRPs and Ryr1 is both necessary and sufficient for preserving NMJs that lack Schwann cells. These findings suggest that muscle activity mediated by DHPRs/Ryr1 may destabilize developing NMJs and that Schwann cells play crucial roles in counteracting such a destabilizing activity to preserve neuromuscular synapses during development.
Highlights
Like all chemical synapses in the brain, the neuromuscular junction (NMJ)–the synaptic connections between motor neurons and skeletal muscles–is assembled as a tripartite structure that includes a presynaptic motor nerve terminal, a postsynaptic muscle cell and a terminal Schwann cell, which caps the motor nerve terminal
These findings suggest that muscle activity normally destabilizes the NMJ during synapse formation and that Schwann cells play crucial roles in NMJ formation by opposing this muscle-derived destabilizing activity in order to preserve the developing neuromuscular synapses
Genetic rescue of neuromuscular synapse loss by postsynaptic acetylcholine receptors (AChRs), because genetic elimination of muscle-specific AChRs in CRD-Nrg1−/−mice rescued muscle denervation. We show that these effects were mediated through muscle activity because genetically ablating either dihydropyridine receptors (DHPRs) or ryanodine receptor 1 (Ryr1) rescues muscle denervation and neuromuscular synapse loss in CRD-Nrg1−/−mice
Summary
Like all chemical synapses in the brain, the NMJ–the synaptic connections between motor neurons and skeletal muscles–is assembled as a tripartite structure that includes a presynaptic motor nerve terminal, a postsynaptic muscle cell and a terminal Schwann cell, which caps the motor nerve terminal. Deficiencies in NRG1/erbB signaling–as shown in CRD-Nrg1−/−, erbB2−/−and erbB3−/−mutant mice–lead to a loss of Schwann cells and, a retraction of motor nerve terminals from diaphragm muscle, resulting in muscle denervation and neuromuscular synapse loss [37,38,39,40,41,42,43]. These defects are likely due to the loss of Schwann cells, rather than a loss of NRG1/erbB signaling from motor neurons to muscles, since deleting erbBs in muscles does not affect NMJ formation and function [44]. How an absence of Schwann cells may cause muscle denervation and neuromuscular synapse loss, remains unclear
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.