Validating a novel target for correction of pathophysiology in fragile X and TSC

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DESCRIPTION (provided by applicant): Several genetically defined developmental disorders that manifest as autism and intellectual disability, such as fragile X (FX) and tuberous sclerosis complex (TSC), have in common a disruption of activity-regulated protein synthesis at synapses. Understanding how neural activity regulates synaptic protein synthesis is crucial for identifying new therapuetic approaches for these diseases. One key mechanism employs metabotropic glutamate receptor 5 (mGluR5) but it remains to be established how this receptor couples to the mRNA translation machinery. Here we test the hypothesis that a crucial link between mGluR5 and protein synthesis is provided by ß-arrestin. Our specific aims are to characterize the effect of ss-arrestin genetic reduction on (1) mGluR5 signaling and protein synthesis in the hippocampus using biochemical methods, (2) hippocampal synaptic function and protein synthesis-dependent plasticity using electrophysiological methods, and (3) on fragile X behavioral and electrophysiological phenotypes expressed in the Fmr1 knockout mouse. If our hypothesis is correct, we expect to observe an amelioration of fragile X phenotypes by reducing ß-arrestin, validating the mGluR5-ß-arrestin protein complex as a novel therapeutic target.