Our long term objectives are to understand the cellular mechanisms by which synapses are eliminated at the neuromuscular junction. During normal development of the nervous system, more synapses are initially formed than will persist to adulthood. The withdrawal of some synaptic connections plays an important role in shaping the final """"""""wiring diagram"""""""" of the nervous system, and consequently it is important in shaping the functional capabilities of all higher animals. There is good evidence that the converging synapses are competing with each other in some way, but the cellular mechanisms underlying the competition are unknown. We have observed in preliminary studies that when two axons converge upon a single muscle fiber, stimulation of one nerve can depress the amplitude of the synaptic potential produced in response to stimulation of the other nerve. The depression appears to be maximal about 30 milliseconds after the conditioning stimulus, and lasts about 100 milliseconds. We propose to investigate the physiological basis of this interaction by studying the effects of various drugs and ions on the interaction. In addition, we will study the morphological relations between nerve terminals with the electron microscope, after selectively labelling some of the nerve endings with horseradish peroxidase. We also have begun to develop an in vitro preparation of spinal cord, peripheral nerve, and muscle, all dissected in continuity. We propose to characterize this preparation in more detail. If synapse elimination can be reliably detected, as preliminary observations suggest, we will then be able to study the cellular mechanisms of synapse elimination by altering the composition of the bathing medium and the electrical activity of the nerves to the muscle.
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