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

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Summary

Introduction

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

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