SUMMARY The underlying brain defects in Fragile X Syndrome (FXS) are not well understood. We have been investigating the specific circuit alterations that lead to a variety of symptoms in FXS, including attention deficit, anxiety, hyperarousal, sensory hypersensitivity and delayed learning. We focus on FXS, the most common inherited cause of autism and intellectual disability, because most investigators use the same Fmr1 knockout mouse model to investigate it, and because it lacks neuropathological features that often confound investigations in other neurodevelopmental disorders (e.g., severe epilepsy, neuronal migration defects, etc.). We strive to overcome limitations of previous studies by comparing the performance of humans and mice with FXS on analogous behavioral tasks. Our goal is to identify shared deficits in sensory processing and learning across both species that will hopefully improve outcomes of future clinical trials in FXS. Here, we will determine the impact of sensory distractors on behavioral performance in both humans and mice using a visual discrimination task. We will also identify specific alterations in population dynamics of pyramidal neurons and different subtypes of inhibitory interneurons that are responsible for deficits in sensory discrimination in Fmr1 knockout mice. Building on our recently published study in Nature Neuroscience (Goel et al., 2018), we will address the following important questions: 1. Does distraction worsen performance in a sensory discrimination task in Fmr1 knockout mice and in adult subjects with FXS? (Aim 1)? 2. Is the firing of parvalbumin (PV)- and vasoactive intestinal polypeptide (VIP)-expressing interneurons disrupted in Fmr1 knockout mice during the sensory discrimination task, especially in the presence of sensory distractors? (Aim 2A)? 3. Can silencing VIP interneurons (or exciting PV neurons) with DREADDs rescue behavioral performance in Fmr1 knockout mice? (Aim 2B)? 4. Do mice and humans with FXS share similar deficits in neural oscillations (Aim 3)? The mouse studies will be performed in the laboratory of established FXS investigator Carlos Portera-Cailliau (PI) at UCLA. Craig Erickson (co-I), who runs the world’s 3rd largest FXS clinic at the University of Cincinnati, will conduct the human studies. The experimental design exploits cutting edge in vivo imaging techniques (e.g., chemogenetics, in vivo two-photon calcium imaging, Cre-Lox genetics, silicon probe recordings, phase- amplitude coupling analysis of EEG) and seeks to address important knowledge gaps in ASD pathogenesis.