EXPRESSION AND FUNCTION OF FMRP DURING DEVELOPMENT

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Our laboratory has recently obtained evidence from an in vitro synaptoneurosome preparation that the fragile X gene product, a protein termed FMRP, is translated from mRNA at locations near synapses in response to glutamatergic activation of metabotropic receptors. This finding complements other work on the fragile X gene (FMR-1) and the fragile X syndrome, a form of mental retardation correlated with the absence of normal FMRP expression, all of which suggest that FMRP may play a role in the process whereby synaptic activity during development and/or learning results in a structural and functional maturation of the synapse. We propose a series of basic studies of the rodent brain designed to further explore in vivo, 1) the spatio-temporal pattern of the expression of FMRP during development, 2) the possible correlation of FMRP expression with other major developmental processes, such as synaptogenesis, in order to explore possible reasons for the pathological effects of FMRP deficiencies on brain development, and 3) the effects of behavioral experience on FMRP expression in brain regions known to exhibit structural plasticity in response to behavioral experience manipulations, studying visual cortex in monocularly deprived animals and animals exposed to an enriched environment, and motor cortex in animals after acrobatic motor skill learning. Fragile X syndrome, which can arise from a mutation that prevents gene expression or from point mutations affecting the structure of the gene product, is one of the most common forms of inherited mental retardation known. Furthermore, it is commonly associated with autism and attention deficit hyperactivity disorder. Knowledge of the role of FMRP in synapse maturation and brain function may well give rise to treatments for these syndromes.