Fragile X syndrome (FXS) is the most common single gene cause of autism and intellectual dysfunction. It is marked by devastating alterations in cognition and behavior that originate in infancy. Approximately 1 in 4000 live births are affected by the disorder; therefore it represents a major health problem that also profound impacts a sizeable number of military families. A core symptom of the disorder is hypersensitivity of the senses including hypersensitivity to touch, such that normal sensory stimuli are perceived as aversive. This contributes directly to many of the challenges faced by FXS individuals, including hyperarousal, social withdrawal and anxiety. The two partnering laboratories have collaborated on understanding this disruption for a number of years by working on an experimental mouse model of FXS. Studies from our laboratories have begun to define how the development of synapses and circuits in the sensory cortex are altered in FXS. We have found that there is abnormal activity in parts of the brain that process sensory inputs that could be due to changes in the neurotransmitter GABA, which normally dampens brain activity. In this proposal we will determine the extent of the alteration in synapses, neurons, circuits and behavior in the FXS model and ask the following three questions: 1) how do changes in the activity of neurons in the brain of FXS mice lead to an altered response to touch? 2) what are the alterations in GABA and brain connectivity that lead to a difference in the response of neurons in the circuit? 3) can we fix the problems in the aberrant response to touch in mice by improving GABA signaling during early brain development? These studies are designed to understand a critical problem in the FXS 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 touch sensation. Our experimental design will employ cutting-edge techniques to record from neurons in the sensory cortex and is designed to incorporate the complementary expertise of the partnering laboratories. The ultimate outcome will be in identifying the network basis for hyperarousal to sensory stimuli, a hallmark symptom in FXS, and will inform the future development of novel treatments for children with FXS.
|Effective start/end date||7/1/17 → 12/31/20|
- U.S. Army Medical Research and Materiel Command (W81XWH-17-1-0230)
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