Cortical circuit dysfunction in fragile x syndrome

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 DESCRIPTION (provided by applicant): The identity of cortical inhibitory microcircuits responsible for cognitive dysfunction in neurodevelopmental disorders remains largely unknown, despite their capacity to control and regulate network synchrony in the brain at behaviorally relevant frequencies. Fragile X Syndrome (FXS) is a neurodevelopmental disorder characterized as the leading monogenetic cause of intellectual disability and autism. While many studies focus on excitatory circuit dysfunction, many aspects of the FXS phenotype point to problems associated with inhibitory neurotransmission defects such as increased incidence of recurring seizures, social anxiety and hypersensitivity to sensory stimuli. Our recently published work illustrates defective activation of somatostatin-positive low-threshold spiking (Sst-LTS) inhibitory interneurons in a mouse model of FXS. We will now use a multidisciplinary approach merging electrophysiology, behavior and optogenetic technology with genetic rescue mice to study how a defective population of interneurons affects cellular, circuit and behavioral properties in FXS. The collective goal of these experiments is to determine how fluctuations in inhibitory function of cortical circuits affect both pharmacologic and network plasticity. Specific Aim 1 will identify the multiple mechanisms by which faulty activation of Sst-LTS interneurons alters cellular function and communication between Sst-LTS interneurons and their targets. Specific Aim 2 will study large scale network properties that require fully functional interneurona microcircuits. Our findings will provide the basis for new and important areas of investigation into the relationship between cortical interneurons and the roles they play in the plasticity of disease. Moreover, these studies will aid in the elucidation of potential therapeutic strategies fo the corrective restoration of cognitive and behavioral deficits observed in the FXS phenotype.