The main goal of this work is to better understand a curious naturally occurring phenomenon: the widespread loss of synaptic circuits in the developing nervous system. This withdrawal, known as synapse elimination, occurs in early postnatal life and has the effect of redistributing a neuron's synapses so that it strongly activates a subset of its synaptic partners while, at the same time, completely disconnecting from the rest. Several lines of evidence suggest that early experience may play a role in deciding which connections are maintained and which are lost. Therefore, this phenomenon may provide insight into the still largely mysterious ways in which experience causes long lasting alterations in the function of the brain, i.e., the changes that underlie learning and memory. In order to study this phenomenon, mice have been engineered that express different color fluorescent proteins in individual neurons. Time lapse imaging of neuromuscular synaptic connections in living mice will permit direct visualization of the details of how one neuron's connections compete with others and what the consequences of the competition is for both the losing inputs and those that are maintained. In addition, confocal imaging will be used to generate, for the first time, a complete three-dimensional reconstruction of the entire branching pattern of an axon that is in the process of losing some of its connections. To get at the ultrastructural basis of nerve detachment and withdrawal from target cells, serial electron microscopic three-dimensional reconstruction of the inputs to a cell that are engaged in competition will be carried out throughout the postnatal period of synapse elimination. Lastly, using a new technique, the migration of neurotransmitter receptors will be tracked during the process of synapse elimination. Because our present understanding of the basic mechanisms that regulate synapse maintenance and elimination is so rudimentary, the way in which synaptic connections are altered in disease is not understood. It is hoped that these experiments will provide essential and fundamental insights into the cell biological phenomena that regulate synapse number and distribution in the nervous system.
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