The long-term objectives of this research are to elucidate basic cellular and molecular mechanisms of synaptic function, formation, remodeling and maintenance. The present proposal aims to reveal novel roles of the perisynaptic Schwann cell (PSC), a synapse-associated glial cell, by testing the following hypotheses regarding synapse-glial interactions at the frog neuromuscular junction (NMJ):(1) To test the hypothesis that PSCs are required for the maintenance and sprouting of adult NMJs. A novel technique using complement-mediated lysis to selectively ablate PSCs in vivo will be applied to study the effect of PSC ablation on maintenance of synaptic structure (presynaptic nerve terminals and postsynaptic acetylcholine receptors), and on nerve terminal sprouting. (2) To test the hypothesis that PSCs modulate synaptic transmission at adult NMJs. Both short- and long-term effects of PSC ablation on synaptic function (endplate potentials, paired-pulse facilitation and synaptic depression) will be examined with intracellular recording. (3) To test the hypothesis that PSCs promote the formation and function of developing NMJs in vivo. The effects of in vivo PSC ablation on synaptic growth and transmitter release will be examined in tadpole and young frog muscles. (4) To test the hypothesis that Schwann cell-derived factors promote the formation and function of developing NMJs in vitro. The effects of Schwann cell-conditioned medium on synaptic physiology and morphology will be examined in nerve-muscle cultures.The proposed research will use both in vivo and in vitro approaches to test an emerging concept that glial cells tell neurons to build larger, stronger and more stable synapses. The insights into the mechanism of synapse-glial interactions will contribute to a better understanding of neuromuscular diseases and axonal regeneration after trauma, as well as development and plasticity of the nervous system.
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