A multi-disciplinary approach is proposed in this Program Project to identify and characterize the basis by which the synapsin family of phosphoproteins promote synaptogenesis and stabilize synapses. A greater understanding of the molecular mechanisms which underlie the trophic actions of the synapsins may lead to novel therapeutic targets for the treatment of Alzheimer's disease. To define the trophic function of the synapsins in synapse formation and maintenance, studies will be performed at several levels of organization complexity, encompassing in vitro biochemical studies with purified molecules, cell biological systems, and studies in intact animals Project I will focus on elucidating the mechanisms by which the synapsins regulate the temporal expression and spatial organization of cytoskeletal and synaptic proteins during synaptogenesis and synapse stabilization. Immunocytochemical and biochemical analyses will be used to assess the effects of targeted deletion of the synapsins, and the expression of mutant synapsins, in primary neuronal cultures. Project II will characterize the mechanisms by which the synapsins act as downstream effectors in the signal transduction cascade that is activated by the neurotrophins. The phosphorylation of the synapsins by MAP kinase, the physiological regulation of this kinase by the neurotrophins, and the functional consequences of this phosphorylation will be studied in vitro and in vivo. Project III will examine the effects of altered synapsin expression on neural degeneration and reactive synaptogenesis in animal models. We will compare wild-type mice with aged mice and with which have been experimentally modified by targeted genetic alterations and by physical/chemical insults. A Core facility will provide a range of technical support services to the other components of the Program Project. The Core will be responsible for the preparation and maintenance of key reagent, and will maintain the colonies of genetically altered mice.
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