This is a five-year plan to continue our research on the molecular and cellular events associated with (1) the growth and orientation of nerve processes, (2) the secretion of acetylcholine (ACh) and other factors from the nerve terminal before and after the contact with its target muscle cell, (3) the early nerve-muscle interactions and the maturation of neuromuscular synapse. These events will be studied in Xenopus nerve- muscle cultures, using a combination of techniques from electrophysiology, biophysics, and cell biology. We will address problems associated with three different stages of neural development. First, for the period of nerve growth, we will examine the effect of neuronal activity on neurite extension, the relationship between neurite extension and transmitter secretion, and the role of cytoplasmic second messengers, Ca2+ and cAMP in particular, in regulating the secretion and orientation at the growth cone. Second, for the early period of synaptogenesis, we will study the neuronal responses to muscle contact, the involvement of ACh receptors in nerve- muscle interactions, and the secretion of calcitonin gene-related peptide from the nerve terminal. Third, for the period of synapse maturation, we will survey the structural and functional changes associated with synaptic maturation, examine the role of second messenger systems in regulating these changes, and test the hypothesis that synaptic activity affects the development and stability of the synapse through direct electrokinetic actions exerted by the synaptic currents on the distribution of cellular components. The result of this research will help us to understand the molecular aspects of nerve growth, transmitter secretion and formation of synaptic connections.
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