Description:

For many years, our work has focused on the development and maintenance of the neuromuscular junction. Our very recent study of the antimalaria drug mefloquine (Lariam) suggests that spontaneous and stimulus-evoked release of transmitter are differentially regulated at the adult neuromuscular junction. That is, mefloquine selectively increases spontaneous, but not stimulus-evoked, vesicular release. This effect of mefloquine is dependent upon intracellular but not extracellular calcium. The source of this intracellular calcium may be mitochondria of motor nerve terminals since mefloquine, like oligomycin, inhibits the F1F0 H⁺ ATP synthase of these organelles. Thus, our working hypothesis is that asynchronous transmitter release may be part of an energy sensing system essential to the health and stability of the neuromuscular junction. While this hypothesis is important to the long-term goal of our work, it is highly relevant to our studies of diabetes. In diabetes the neuromuscular junction undergoes deleterious morphological and functional alterations. It is conceivable that these changes are secondary to diabetes-induced alterations of energy balance at the neuromuscular junction.

Current progress:

In order to study the role of mitochondria in synaptic function, we have begun a collaboration with the BioCurrents Research Center. There are two objectives of this collaboration. Our collaboration allows novel and fundamentally important studies of synaptic energy consumption using the group's expertise in measuring O₂ consumption with high temporal and spatial fidelity. Further, this allows us to image mitochondria at the neuromuscular junction. The facilities and equipment for such studies established at BRC are unmatched anywhere else in the world. As a result of this collaboration, we are able to bring cutting edge technology to the study of fundamental questions which have relevance to diabetes, Amyotrophic Lateral Sclerosis, and nerve injury repair.