This work is directed at understanding the process whereby neurons sever their connections with some of the target cells they make contact with in development. Experiments indicate that the loss of connections is the consequence of a protracted competition between the synapses of different neurons vying to remain connected to the same target cell. In addition it is likely that the activity of each axon plays a role in destabilizing the connections of its competitors. Because neural activity is instrumental in the process leading to elimination of synaptic connections, the mechanisms underlying this loss may be an important part of the process whereby experience may alters the brain in a permanent way as occurs in development and in the formation of memories in adults. This proposal focuses on two simple and accessible synaptic regions that undergo the competitive loss of neuronal input--the neuromuscular junction and synapses on parasympathetic neurons. As previous work has shown that the target cell may be an intermediary in the competition between inputs, many of these studies attempt to provide a better understanding of how and why the target cell is changed during and after synaptic loss. To get a more detailed picture of the minute by minute behavior of competing axons, nerve terminals labeled in living animals will be followed over long periods as synapse loss is occurring. To see if nerve terminal activity mediates synaptic competition through the release of neurotransmitter, experiments that attempt to mimic competition with localized release of neurotransmitter in a culture dish are proposed. Lastly to see whether the mechanisms underlying the loss of synapses in muscle that has already been described is the same as the process that occurs in parasympathetic ganglia, experiments which study changes in the structure and function of soon-to-be eliminated synapses in ganglia are proposed. These results will be useful in the attainment of a full understanding of this key developmental process. Because learning disorders and memory impairments are common but at present almost entirely without rational treatment, the kind of basic information this proposal aims to provide concerning how synapses change is likely to be useful.
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