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Increased Probability of Release in Huntington's Disease Neuromuscular Junctions
Author(s) -
Khedraki Ahmad,
Reed Eric Joshua,
Rich Mark M.,
Voss Andrew Alvin
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.992.2
Subject(s) - denervation , skeletal muscle , neuromuscular junction , neuroscience , stimulation , neuromuscular transmission , huntington's disease , electrophysiology , voltage clamp , biology , medicine , chemistry , anatomy , disease
Huntington's disease (HD) is a progressive and fatal degenerative disorder that results in debilitating cognitive and motor dysfunction. The majority of research related to HD has been focused on neurodegeneration in the central nervous system. Recently, we discovered defects in the membrane properties and mRNA processing of skeletal muscle from the R6/2 transgenic mouse line of HD. The decrease in the resting chloride and potassium conductance result in hyperexcitable skeletal muscle that is hypersensitive to neuronal stimulation. The objective of this study was to examine the neuromuscular events that trigger muscle excitation. We used a fully innervated ex vivo preparation of the levator auris longus muscle from late‐stage R6/2 mice and age‐matched wild type controls. Our voltage clamp records of spontaneous miniature endplate currents (mEPCs) and nerve‐evoked endplate currents (eEPCs) were independent of the changes in muscle membrane properties, unlike previous current clamp studies. Using the charge moved during the mEPCs and eEPCs, preliminary data indicates that the number of vesicles released per action potential (quantal content) was not significantly different between HD and WT muscle. This argues against denervation/renervation, which has been suggested in other studies. Furthermore, in response to trains of nerve stimulation (10 action potentials at 50 Hz), eEPCs in HD muscle reached a peak amplitude sooner and then depressed to a greater degree than in WT. This amplified depression suggests an increased probability of vesicle release in HD neuromuscular junctions. This hypothesis was supported by data obtained under low Ca 2+ and high Mg 2+ extracellular conditions, where quantal content in HD is higher than in WT. Because studies of central synapses face more experimental limitations, our voltage clamp examination of neuromuscular transmission is hitherto the most complete analysis of synaptic function in HD. The defects we discovered serve as a model to understand the contribution of synaptic defects to the devastating cognitive and motor symptoms in Huntington's disease. Support or Funding Information Wright State University Startup to AAV.