My laboratory studies mitochondrial function in motor neuron terminals at the neuromuscular junction of adult mice, using electrophysiological and fluorescence imaging techniques. We demonstrated that motor terminal mitochondria sequester calcium during trains of action potential stimulation, and that their subsequent extrusion of this sequestered calcium contributes to a form of synaptic plasticity called post-tetanic potentiation. Work in our and other laboratories indicates that mitochondrial dysfunction has a major role in the motor neuron death associated with amyotrophic lateral sclerosis (ALS), and that some of the earliest dysfunction may occur in motor neuron terminals. We demonstrated in motor terminals of ALS model mice (1) abnormal sequestration of stimulation-induced Ca2+ loads, (2) increased mitochondrial depolarization and (3) transient opening of the mitochondrial transition pore. We also showed that perfusing leg muscles with a mitochondrial-protective agent (methylene blue) helps preserve motor nerve terminals and muscle function in an ALS mouse model. These findings suggest that strategies aimed at preserving mitochondrial function in motor nerve terminals may be helpful in delaying the motor neuron death that occurs in ALS. This work is in collaboration with Drs. John Barrett and Gavriel David.
