The majority of Fragile X individuals suffer from mental disabilities, suggesting that cognitive impairment is a central problem in Fragile X syndrome (FXS). There is no known cure. Hope for a treatment is plausible though, since patient neurons do not appear damaged or destroyed.

In fact, the neuronal circuitry that is largely formed before birth is grossly normal in Fragile X patients, and it is the fine synaptic connections, the structural sites for neurotransmission between neurons, that appear disrupted in FXS.

These synaptic connections, and their modification by experience, are thought to underlie the fundamental mechanisms of cognitive functioning. Given that synaptic connections are highly plastic after birth and remain so in Fragile X, we believe that drugs that can correct the disease will work by influencing the components that regulate synaptic connectivity. In this research project, we will begin to test this hypothesis by developing a high-throughput assay that specifically studies the synaptic connectivity defects underlying FXS and is suitable for drug discovery.

One type of high-throughput assay, High-Content Screening (HCS), is capable of reporting on subtle features of cultured neurons including changes in synaptic connectivity. In this research project, we will use HCS to develop an assay sensitive to the effect of the FXS genotype (validation step 1), and then to test the ability of an mGluR5 antagonist in restoring the effects of the FXS genotype to normal in this assay (validation step 2). Once validated, this HCS assay will be used to screen existing Food and Drug Administration (FDA)-approved compounds for effectiveness in Fragile X. Results from this project would establish the first cell-based morphological and functional tool directly relevant for treating the neuronal deficits underlying cognitive impairment in FXS and would bridge the gap between basic synaptic/cellular biology and preclinical animal model testing. Moreover, since several collections of FDA approved drugs have proven to be rich sources of undiscovered bioactivity and therapeutic potential, drugs discovered to treat mental impairments in this HCS assay may have immediate application to treatment of FXS and may also help treat autism.