Fragile X Syndrome (FXS) is the most common inherited form of mental retardation and is caused by loss of function mutations in the Fmr1 gene. Approximately 30% of FXS patients are diagnosed with autism, and 2-5% of all autistic children have FXS. As result, Fmr1 is currently one of 3 most strongly linked genes to autism. Therefore, the mouse model of FXS may be useful in determining what causes or facilitates autism in humans. Virtually nothing is known about how the protein product of Fmr1, FMRP, or its loss, affects the development and function of brain circuitry. Dr. Huber's lab utilizes electrophysiological methods that directly measure the electrical-chemical nature of neuronal communication in brain circuitry. The primary means of communication in brain circuits is the excitatory synapse. It is well established that synapses are plastic, in that they can alter their size, strength and number in both developing and adult brains. Dr. Huber's preliminary experiments provide evidence that excitatory synaptic communication is dramatically decreased in the Fmr1 mutant mouse brain during development. In this project the researchers will further characterize this phenomenon, identify the specific components of the excitatory synapse that are responsible for the decrease in synaptic communication, and test whether intervening with the molecular pathways will reduce the synaptic deficits found in the FXS mouse model. What does this mean for people with autism: Further understanding of the synaptic impairments is critical for designing treatments and cures for FXS and perhaps autism. Identification of the molecular mechanisms that affect brain circuitry in a model of autism will directly lead to identification of therapeutic targets.