Pathophysiology and treatment of fragile X and related disorders

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Currently there are no mechanism-based therapies available for autism spectrum disorders (ASDs) and intellectual disability (ID). Two major barriers are the identification of defective cellular processes within the brain that disrupt behavior and cognition, and the validation of an objective biomarker based on pathophysiology that can be used for patient stratification and assessing treatment response. The objectives of this project are to address these deficiencies using the mouse model of fragile X syndrome, a leading cause of human ID and ASD. Fragile X is caused by silencing of the FMR1 gene on the X chromosome and loss of the encoded protein FMRP. Major consequences of the loss of FMRP include disrupted regulation of protein synthesis in neurons, altered ion channel function, and altered development of inhibitory circuits in the cerebral cortex. Previous studies in the Fmr1 KO mouse showed that manipulations that acutely correct alterations in basal protein synthesis also improve a wide variety of structural, biochemical, and behavioral deficits. Thus, one promising line of research entails understanding how the manipulations of protein synthesis restore normal neuronal function. Our studies in the visual cortex (V1) of Fmr1 KO mice have shown that hyperexcitability of layer (L) 5 V1 neurons is a cell-autonomous phenotype that is corrected by suppressing aberrant protein synthesis. This phenotype may be relevant to sensory hyperresponsivity that is highly disruptive in human fragile X and other forms of ASD, but regardless it is a useful reporter of a functional consequence of altered protein synthesis. Remarkably, reversal of this phenotype occurs rapidly, within 60 minutes of suppressing protein synthesis. These data implicate pathogenic proteins with a short half-life that are rapidly depleted by inhibiting mRNA translation. In Aim 1 of this exploratory project, we will take advantage of genetic access to a subpopulation of L5 neurons to identify these proteins. If successful, this approach will yield a list of novel therapeutic targets specifically linked to aberrant protein synthesis in fragile X. In Aim 2, we will assess the generality of our findings in L5, and investigate the impact of this specific pathogenic mechanism on the function of V1 in awake mice. These experiments will yield novel functional measures of treatment efficacy in vivo that, if translated to humans, could be used as potential biomarkers of a specific class of pathophysiological mechanisms in fragile X and related disorders.