Translation at developing synapses

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

DESCRIPTION (provided by the applicant) Increasing evidence has emerged supporting the idea that many more CNS synapses are made than are eventually retained, and that this phenomenon includes a process of synapse specification in which certain sites become stabilized and others are lost. Although recent work supports that young synapses are structurally and functionally distinct, the processes by which young synapses get stabilized largely remain unknown. Protein synthesis is required for mechanisms of synaptic plasticity such as long-term potentiation (LTP) or depression (LTD), as well as for learning and memory, where synapses are likely to be structurally modified. However, it is not yet known whether the stabilization of newly formed synapses requires protein synthesis. The overall hypothesis of this proposal is that newly formed synapses are labile structures that require protein synthesis for their stabilization and subsequent maintenance. Treatments that stabilize synapses should render them more resistant to such a requirement than those that destabilize synapses. Ribosomal clustering beneath synapses has been shown to be particularly prominent during development when the capacity for protein synthesis in dendritically enriched neuropil peaks;a general requirement for protein synthesis may thus operate locally. An understanding of the regulation of synaptogenesis and of the differences between dendritic and somatic regulation of protein synthesis has great clinical significance. This link is particularly clear in Fragile X mental retardation where changes in the regulation of dendritic protein synthesis have lasting consequences on synapse morphology and plasticity