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Glial cells maintain synapses by inhibiting an activity-dependent retrograde protease signal

ABSTRACT: We utilized genetic methods to examine how Schwann cells prevent degeneration of motor neurons (MNs) in the spinal cord. Blocking peripheral, neuromuscular activity completely rescued MNs and neuromuscular junctions (NMJs) in erbB3 mutant mice lacking Schwann cells, which normally exhibit profound neurodegeneration. We searched for the molecular basis of this effect by examining the transcriptomes (all of the expressed genes) in the muscle of control mice with Schwann cells and erbB3 mutant mice without them. We found evidence that a negative signal expressed by muscle was regulated by neural activity and normally blocked by factors produced in Schwann cells. When we eliminated this activity-induced negative signal (thrombin) from muscle, MNs and NMJs were protected in erbB3 mutants, similar to the effects of eliminating activity. Together, these results suggest that Schwann cells prevent neurodegeneration by inhibiting the effect of activity-induced, muscle-derived negative factors, rather than by providing trophic positive factors.

ORGANISM(S): Mus musculus

PROVIDER: GSE125490 | GEO | 2019/03/14

REPOSITORIES: GEO

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Project description:Desmin, the major intermediate filament (IF) protein in muscle cells, interlinks neighboring myofibrils and connects the whole myofibrillar apparatus to myonuclei, mitochondria, and the sarcolemma. However, desmin is also known to be enriched at postsynaptic membranes of neuromuscular junctions (NMJs). The pivotal role of the desmin IF cytoskeletal network is underscored by the fact that over 100 mutations of the human DES gene cause hereditary and sporadic myopathies and cardiomyopathies. A subgroup of human desminopathies comprises autosomal recessive cases resulting in complete abolition of desmin protein. In these patients, who display a more severe phenotype than the autosomal dominant cases, it has been reported that some individuals also suffer from a myasthenic syndrome in addition to the classical occurrence of myopathy and cardiomyopathy. Since further studies on the NMJ pathology is hampered by the lack of available human striated muscle biopsy specimens, we exploited homozygous desmin knock-out mice which closely mirror the striated muscle pathology of human patients lacking desmin protein. Here, we report on the impact of the lack of desmin on the structure and function of NMJs and on the transcription of genes coding for postsynaptic proteins. Desmin knock-out mice display a fragmentation of NMJs in soleus, but not in extensor digitorum longus muscle. Moreover, soleus muscle fibers show larger NMJs. Further, transcription levels of acetylcholine receptor (AChR) genes are increased in muscles from desmin knock-out mice, especially of the AChR subunit, which is known as a marker of muscle fiber regeneration. Electrophysiological recordings depicted a pathological decrement of nerve-dependent endplate potentials and a faster rise time of the nerve-independent miniature endplate potentials. The latter is indicating an enhanced opening time of the AChR channels. Our study highlights the essential role of desmin for the structural and functional integrity of mammalian neuromuscular junctions.

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Glial cells maintain synapses by inhibiting an activity-dependent retrograde protease signal

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