The synapsins are a family of four neuronal specific phosphoproteins, the expression of which has been associated with dynamic reorganization of the neuronal cytoskeleton and with trophic actions manifested in axon formation, synapse formation, and synapse maintenance. Synapsins are known to bind and regulate the stability of actin filaments, microtubules, and acidic phospholipids, and synapsin expression alters the expression of several other synaptic proteins. It is unclear, however, which of the synapsin bind activities might be important for the trophic actions of the synapsins, and relatively little is known about the differential contribution of the four synapsin proteins. The long-term objective of this section of the Program Project application will be to learn more about the role of synapsins in axon formation, synapse formation, and synapse maintenance. Specifically, we will focus on the relationship between the cytoskeletal and the genomic effects of synapsin expression, and the relative contributions of the synapsin isoforms to these trophic effects.
Specific Aim 1 will focus on characterizing cytoskeletal dynamics in relation to the temporal expression, spatial distribution, and phosphorylation state of the synapsin isoforms. Cultures of primary hippocampal neurons from wild type and synapsin knock out mice will be used to determine how the normal steps in cytoskeletal development and synaptogenesis are affected by deletion of synapsin I, synapsin II, or synapsin I and II.
Specific Aim 2 will focus on determining which of the synapsin binding activities are important during neuronal differentiation. Synapsins which contain deletions in one or more of the bind domains will be reintroduced into cultures from synapsin knock out mice and the ability of the mutant synapsins to rescue the developmental defects will be assessed.
Specific Aim 3 will focus on determining the mechanism whereby synapsin levels regulate the expression levels of other synapsins and of synaptic proteins. Finally, Specific Aim 4 will focus on determining whether the ability of the synapsins to regulate expression of other proteins is dependent on their ability to induce cytoskeletal reorganization.
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