This proposal is aimed at determining the role of neurotrophins that signal through Trk receptors in modulating synapse structure and function in the developing and adult nervous system, using mouse neuromuscular synapses as a model system. The cell types that comprise neuromuscular junctions, the perisynaptic Schwann cells, presynaptic motor neuron terminals, and postsynaptic muscle fibers, each express a distinct complement of neurotrophins and Trks This suggests that neurotrophin signaling at this synapse is multi-directional and involves all three cell types, but the relative roles of each signaling pathway in synaptic structure and function are unclear. Previous work from the Balice-Gordon lab has shown that TrkB, which binds the neurotrophins BDNF and NT4/5, is expressed primarily postsynaptically in the muscle fiber membrane adjacent to acetylcholine receptor (AChR) clusters. Down-regulation of TrkB signaling in muscle fibers induced the disassembly of AChR clusters. These observations lead to the hypothesis that exchange of ligands that signal through TrkB receptors modulates neuromuscular synaptic structure and function. To determine the role of these signaling molecules at synapses, it will be essential to selectively delete TrkB or neurotrophin from one of the cell types at neuromuscular synapses. Because many null mutant mice die perinatally, I propose to use Cre-mediated recombination to delete BDNF or TrkB from cells of interest in a spatially and temporally controlled fashion The effects of these deletions on neuromuscular synaptic structure, function, axon regrowth and synaptic reinnervation after injury will be analyzed with in vivo imaging, immunostaining, confocal microscopy and electrophysiological characterization of synaptic strength. The results of these experiments will provide new insights into the functional roles of neurotrophin and Trk-mediated signaling at developing, adult and injured synapses.
|Hess, Darren M; Scott, Marion O; Potluri, Srilatha et al. (2007) Localization of TrkC to Schwann cells and effects of neurotrophin-3 signaling at neuromuscular synapses. J Comp Neurol 501:465-82|
|Pitts, Elizabeth Vernon; Potluri, Srilatha; Hess, Darren M et al. (2006) Neurotrophin and Trk-mediated signaling in the neuromuscular system. Int Anesthesiol Clin 44:21-76|
|Su, Yuhua; Balice-Gordon, Rita J; Hess, Darren M et al. (2004) Neurobeachin is essential for neuromuscular synaptic transmission. J Neurosci 24:3627-36|