Tracking the Progression of Defects at the Neuromuscular Junction in Huntington's Disease
Abstract
Huntington’s disease (HD) is a genetic disorder associated with progressive cognitive and motor decline. Recent studies in HD models suggest primary peripheral pathologies arise independent of changes in the central nervous system. Our lab found defects in skeletal muscle occurring early in the progression of disease in transgenic R6/2 HD mice, resulting in membrane hyperexcitability. Additionally, there is evidence of decreased quantal content in late-stage R6/2 mice. Here, we investigate pre-synaptic and post-synaptic function at single neuromuscular junctions (NMJ) to make direct comparisons of disease progression in the muscle membrane and motor nerve terminal. We hypothesize that muscle membrane defects will precede reductions in neuromuscular quantal content during the progression HD in R6/2 mice. Muscle membrane properties and synaptic transmission were measured in 8-, 10-, and 12-week R6/2 mice. Identifying the earliest pathological influence of dysfunction at the NMJ may provide targets for treatment of motor symptoms in HD.
