Slow-Channel Transgenic Mice: A Model of Postsynaptic Organellar Degeneration at the Neuromuscular Junction

Abstract

The slow-channel congenital myasthenic syndrome (SCCMS) is a dominantly inherited disorder of neuromuscular transmission characterized by delayed closure of the skeletal muscle acetylcholine receptor (AChR) ion channel and degeneration of the neuromuscular junction. The identification of a series of AChR subunit mutations in the SCCMS supports the hypothesis that the altered kinetics of the endplate currents in this disease are attributable to inherited abnormalities of the AChR. To investigate the role of these mutant AChR subunits in the development of the synaptic degeneration seen in the SCCMS, we have studied the properties of the AChR mutation, ⑀L269F, found in a family with SCCMS, using both in vitro and in vivo expression systems. The mutation causes a sixfold increase in the open time of AChRs expressed in vitro, similar to the phenotype of other reported mutants. Transgenic mice expressing this mutant develop a syndrome that is highly reminiscent of the SCCMS. Mice have fatigability of limb muscles, electrophysiological evidence of slow AChR ion channels, and defective neuromuscular transmission. Pathologically, the motor endplates show focal accumulation of calcium and striking ultrastructural changes, including enlargement and degeneration of the subsynaptic mitochondria and nuclei. These findings clearly demonstrate the role of this mutation in the spectrum of abnormalities associated with the SCCMS and point to the subsynaptic organelles as principal targets in this disease. These transgenic mice provide a useful model for the study of excitotoxic synaptic degeneration.

Increased neuromuscular activity causes axonal defects and muscular degeneration

“…Although we have not determined whether the αL258P mutation renders the AChR channel leaky, the severe myofibril and AChR cluster defects observed in 17-hpf homozygous mutants, despite the presence of only few synaptic contacts, are consistent with the possibility that nic-1 twister dbn12 channel opens extensively in a ligand-independent manner. Regardless of the precise mechanism, our results demonstrate that the onset of progressive end-plate and myopathy can occur during embryogenesis, much earlier than previously reported in SCCMS patients or SCCMS mouse models (Engel et al, 1982;Engel et al, 2003;Gomez et al, 1997). Thus, as growth cones make their first contacts with the muscle, increased channel activity impacts ongoing pre-and post-synaptic development.…”

T-cell TGF-β signaling abrogation restricts medulloblastoma progression

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