The objective of this research is to understand how developing neurons form synapses onto particular neurons to form a functional neuronal circuit. These mechanisms will be studied in a relatively simple nervous system--that of the medicinal leech--because many of its neurons can be identified even before they start to grow the processes that will be the sites of synapses. In addition, a great deal is known about the morphological and physiological properties of these identifiable neurons, including the role that many of them play in generating behavior. Experiments will focus on the development of connections in two well-defined neural circuits: the connection between a pair of identified motor neurons, both of which innervate the same muscles in the body wall, and the connections in a reflex pathway that includes a sensory receptor, an effector neuron, and an intervening layer of a small number of interneurons. The generation of specificity will be approached using the following techniques: detailed morphological examinations of the spatial relationship between neuronal branches as the contacts are first established; physiological recordings from the synaptic connections as they form; and ablations of single neurons, of branches of neurons, or of peripheral targets, to perturb the environment in which the neurons are developing. These experiments will determine which mechanisms are operating in this well-defined system. For example, we will test whether neurons form synapses with any other neurons to which they are sufficiently close at a particular time; whether potential synaptic targets respond to environmental signals in a way that puts their branches in close proximity, even though the two neurons are behaving independently of one another; whether competition occurs for synaptic space between neurons that might be eligible to form synapses onto the same neuron; how the peripheral target of a neuron can control which synapses it will accept; and whether electrical activity is important for establishing or maintaining synaptic contacts. Experiments on other species, including higher mammals, have suggested that these same mechanisms control synaptic specificity in humans. The experimental tractability of the embryonic leech nervous system makes it possible to examine how the mechanisms interact to form a functional neuronal circuit among a number of identified neurons in a single species, thereby shedding light on how functional neuronal circuits are established in our own nervous system.
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