NCAM and the polysialic acid (PSA) it carries have been shown to be important for normal neuromuscular development in the chick and have been implicated in the synaptic plasticity associated with learning and memory in the mouse hippocampus. The present studies are designed to determine if NCAM/PSA plays a similar role in the mouse 1) in the correct targeting of motor axons, 2) in regulating intramuscular nerve branching and initial synaptogenesis, and 3) in contributing to the activity dependent and competitive process of neonatal synapse elimination and subsequent synaptic maturation. Electrophysiological analysis of functional synaptic properties and detailed immunolocalization of pre and postsynaptic molecules that have been implicated in synaptic maturation will be carried out in NCAM null mice which are (+/+), (+/-), or (-/-) for the mutation. In addition to making such correlations between the molecular architecture and functions in populations of synapses, the temporal resolutions will be increased by making these correlations at single identified endplates. In addition the dye FM1-43 will be used to achieve better spatial resolution of presynaptic release properties. This dye will also be used in an isolated muscle preparation to study release properties of two inputs during the process of synapse elimination, when they are subjected to different patterns of electrical stimulation over many hours. These experiments are designed to determine if some of the functional interactions between inputs, such as the heterosynaptic depression described in cultured myotubes occurs during in vivo synapse elimination, and to determine if this results in any longer lasting structural alterations of the synapse. Intravascular nerve branching and/or sprouting, and the reformation of effective synapses are required following peripheral nerve injury or loss of neurons in a number of diseases that affect the peripheral motor system. A better molecular understanding of these processes, and how they are affected by electrical activity should aid in designing appropriate strategies for enhancing functional recovery. It is also likely that some of the processes that affect synaptic plasticity at the neuromuscular junction will also be utilized in the central nervous system during regenerative responses and axonal sprouting following injury or the death of neurons as a result of disease.