Dysfunction in Sensory Circuits in Fragile X Syndrome

Fragile X syndrome is the most common inherited form of autism and intellectual disability. It is marked by devastating alterations in cognition and behavior that begin in toddlers. As many as 1 in 4,000 boys in the U.S. are affected by the disorder; therefore, it represents a major health problem that profoundly impacts a sizeable number of military families. Many of the core symptoms of Fragile X arise from altered development of the connections between neurons in the infant brain, with long-lasting consequences in the ability of the brain to process information, leading to many of the challenges faced by individuals with Fragile X, such as sensory hypersensitivity, attention deficit, social withdrawal, delayed learning and anxiety. Our goal is to build upon the past collaborative research of the two partnering laboratories who already discovered that changes in the neurotransmitter GABA in the brain during early developmental affect how the mature brain functions. Using an experimental model of Fragile X they found that early intervention with an FDA-approved drug can restore sensory information processing in the Fragile X brain. This project falls under the FY20 PRMRP Topic Area Fragile X and will identify functional measures of the manifestation of Fragile X, and ultimately identify and test a novel drug treatment in a model system that could eventually be used as a treatment for some of the core symptoms of this devastating disease. These studies are designed to understand a critical problem in the Fragile X field, address important knowledge gaps, and ultimately to determine whether we can find ways to rectify the development of brain circuits that contribute to altered brain activity and the myriad symptoms of the disease. Our experimental design will employ the latest techniques in modern neuroscience to record how neurons in the brain process sensory stimuli. Our experiments incorporate the complementary expertise of the partnering laboratories. The ultimate outcome will be to firmly establish a preclinical mechanism of how Fragile X changes brain function. We are motivated to help patients and their families by discovering new brain targets for treatments that can safely and effectively rectify altered activity in the brain, and thereby address some of the most debilitating symptoms of the disorder in children with this disease.