Project Summary/Abstract. Fragile X syndrome (FX) is a widespread type of inherited intellectual disability. Effective treatments that target mechanisms underlying FX are currently lacking. FX is the foremost monogenic cause of autism spectrum disorders, and thus many individuals with FX exhibit abnormal social behaviors. Individuals with FX also often engage in aberrant spatial behaviors such as “elopement”, wandering off and getting lost. The hippocampus is a brain structure that is particularly vulnerable to FX. Much evidence suggests that hippocampal areas CA2 and CA1 are important for social behaviors and spatial memory, respectively. Yet, few studies have investigated whether disturbances in neurophysiological mechanisms of social and spatial memory functions in CA2 and CA1 underlie social behavioral and spatial memory impairments in FX. This project’s goal is to address this gap in knowledge by investigating the extent to which subcellular, cellular, circuit, and network mechanisms of social and spatial memory operations in the hippocampus are impaired in rodent models of FX. The studies will employ state-of-the-art in vivo and in vitro electrophysiological techniques. In vivo approaches will be used to assess whether aberrant cellular and network mechanisms are related to deficits in social exploration and spatial memory. In vitro experiments will uncover cellular mechanisms underlying altered intrinsic properties and plasticity in CA2 and aberrant inhibition in CA1. Models of FX in two species, specifically Fmr1 knockout (KO) rats and mice, will be used, allowing comparison of FX pathophysiology across species. Specific Aim 1 will assess whether the strength of inputs to CA2 neurons during exploration of social stimuli is weaker in Fmr1 KO rats than wildtype rats. This Aim will also use sophisticated behavioral tracking software to determine whether Fmr1 KO rats show aberrant behavioral patterns during social exploration. Specific Aim 2 will employ whole cell and patch clamp recordings, including recordings directly from dendrites, in hippocampal slices to test whether CA2 neurons in Fmr1 KO rats and mice show impaired synaptic plasticity and responses to the social neuropeptide, oxytocin. Specific Aim 3 will test whether coordination of spike sequences from ensembles of CA1 neurons, believed to be an important network mechanism of spatial memory processing, is disrupted in Fmr1 KO rats performing spatial memory tasks. Coordination of spiking across ensembles of hippocampal neurons requires properly timed activation of specific CA1 interneurons. Thus, disrupted coordination of CA1 spike sequences in FX may reflect disturbances in CA1 interneurons. Specific Aim 4 will employ whole cell recordings of specific classes of CA1 interneurons and inhibitory inputs to CA1 pyramidal cells to test the hypothesis that inhibitory circuits are disrupted in FX. Successful completion of these Aims will provide novel insights about specific mechanisms un...