The Etiology of Fragile X Mental Retardation Syndrome

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DESCRIPTION (provided by applicant): Fragile X mental retardation syndrome is one of the most common heritable forms of mental retardation in humans. The molecular genetic basis of fragile X syndrome has been identified; mutation of the fragile X mental retardation-1 gene(FMR1) leads to a loss of the protein product, the fragile X mental retardation protein (FMRP). Despite our genetic understanding of fragile X syndrome, the biological function of FMRP remains unknown. The role of FMRP can now be studied using the Fmrl-KO mouse, a transgenic model of fragile X syndrome in which FMRP has been genetically knocked out. Recent work in our lab has used these mice to identify a functional role for FMRP in regulating activity-dependent synaptic plasticity in the brain; FMR1-KO mice exhibit increased long-term depression (LTD) of synaptic strength induced by metabotropic glutamate receptor (mGluR) activation. We hypothesize that a lack of FMRP increases mGluR-dependent protein synthesis and/or long-term depression (LTD) in the brain and might be an underlying cause of fragile X mental retardation. Specifically, we aim to test the possibility that the abnormal dendritic spine formation and increased susceptibility to epileptiform activity associated with fragile X syndrome is a direct consequence of inappropriate mGluR regulation. Through this mechanistic link, we hope to account for the morphological, physiological, and behavioral characteristics of fragile X syndrome and to devise strategies for therapeutic treatments.