Neuropeptides are recognized as integral components of information transfer in the central nervous system (CNS). They are widely, but discretely, distributed and subserve a number of physiological and electrophysiological functions. Recent progress in molecular biology has allowed the cloning of the cDNAs and genes encoding the precursor proteins for a variety of neuropeptides yielding information on neuropeptide gene expression, precursor protein structure, and apparent abnormalities in neuropeptide expression in several CNS disorders. Protein biochemical methods have provided information about the post-translational proteolytic processing of neuropeptide prohormones. There is, however, a relative paucity of information regarding the physiological roles subserved by specific neuropeptides in defined terminal fields within the CNS. The proposed research will concentrate on investigations into the role of neuropeptide Y (NPY) in the physiologically and anatomically well-defined system of the hippocampus as one step toward a complete understanding of the regulation of the biosynthesis and metabolism of this neuropeptide. First, the proposed studies will investigate the biosynthesis and post-translational processing of NPY in vivo in normal animals and in animals at specific times following induction of recurrent limbic seizures. Such seizures have been used to demonstrate modulation of NPY gene expression in three defined neuronal populations within the hippocampus: hilar neurons, dentate gyrus granule cells and CA1 pyramidal cells. Second, the biochemical processes that are activated in response to activation of NPY receptors will be investigated in the cell body and nerve terminal fields of these neurons in combination with specific NPY receptor agonist. Third, the possibility that synaptic proteolysis results in additional, biologically active NPY- derived peptide fragments will be investigated. When taken together, the data from the proposed studies will provide essential information regarding the processing and physiological actions of NPY and may shed light on protective cellular mechanisms which are activated in neurons in pathological conditions.
