The long term goal of the research proposed in this application is to understand the mechanisms that underlie the formation of functionally appropriate synaptic connections during development of the nervous system. An important aspect of this process is the determination of the neurotransmitter phenotype of individual neurons. Recently, neuroscientists have recognized that many neurons contain a neuropeptide(s) in addition to a classical neurotransmitter. Neuropeptides have been shown to function as neuro-transmitters or neuromodulators in the adult and some evidence suggests that they may play important roles in development as well. These findings raise the obvious questions of when neuropeptides appear during development and what factors influence the neuropeptide(s) a neuron will express. Preliminary data obtained in studies of rat sympathetic neurons developing in vivo suggest that some neuropeptides appear very early, that individual neurons transiently express multiple neuropeptides, and that experimental manipulation during development can alter peptide phenotype in a striking fashion. Further, we have evidence that peptide function in a class of neurons, parasympathetic ciliary neurons, can be controlled post-translationally. Using immunocytochemidstry and in situ hybridization, we will determine when neuropeptides and the mRNAs that encode them are first expressed in developing sympathetic cells and whether changes in expression occur. By interfering with normal neuron-target interactions, we will examine plasticity of neuropeptide expression and study how peptidergic phenotypes are established in vivo. Finally, we will study the development of processing of one neuropeptide, Neuropeptide Y, in sympathetic neurons and the possible role that processing, packaging and/or transport may play in regulating its function. This latter will be accomplished by using rat ciliary neurons, cells in which these functions can be altered experimentally. The studies proposed will provide important new information concerning the development of neuropeptide expression, processing and transport. They may elucidate the pathogenesis of developmental disorders of the nervous system and of neurodegenerative disease involving peptide dysfunction.
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