Grant: Project Grant

Fragile X Syndrome is the greatest inherited cause of intellectual disabilities and autism spectrum disorder worldwide and yet has no cure. Fragile X occurs at a rate of 1 in 4000 males and 1 in 6000 females, and 1 in ~200 females are carriers that could pass this disorder onto children. The Fragile X mutation leads to the loss of "Fragile X Mental Retardation Protein" (FMRP). Previous work has shown that FMRP regulates the translation of numerous proteins needed to maintain normal synaptic function and plasticity. Because Fragile X is known to reduce synaptic plasticity in cerebellum, we use the mouse cerebellar mossy fiber-granule cell pathway as a model to explore the basis for synaptic abnormalities in Fragile X. Our preliminary data reveal that FMRP binds to an ion channel complex between calcium and potassium channels (Cav3-Kv4) that potentiates the mossy fiber EPSP and increases granule cell excitability via an ERK kinase pathway. We find that FMRP knockout mice completely lack mossy fiber potentiation and associated changes in granule cell excitability. Importantly, intracellular infusion of an active FMRP fragment into granule cells of FMRP knockout mice in vitro restores Cav3-Kv4 function and potentiation of excitability. In addition, an FMRP fragment attached to a tat peptide to facilitate passage across cell membranes rapidly crosses the blood-brain barrier and enters cerebellar granule cells after injection into the bloodstream, opening the door to reintroducing FMRP in live animals. These exciting results provide important steps to understanding a new role for FMRP in controlling a membrane ion channel complex that sets cell excitability, and to assess tat-FMRP as a therapeutic strategy to reduce abnormal behaviour in Fragile X Syndrome.