Circuit pathophysiology, phenotypic heterogeneity and translational electrophysiological biomarkers in mouse models of FXS

Project 2: Circuit pathophysiology, phenotypic heterogeneity and translational electrophysiological biomarkers in mouse models of FXS. Translational biomarkers for Fragile X Syndrome (FXS) were suggested from the findings of our research team that sensory circuits are hyperexcitable in both FXS patients and Fmr1 KO mice, as measured with electroencephalogram (EEG) in mice and humans and in in vitro brain slices. Based on this idea, our team of investigators, working closely together within an NIH Collaborative Center for Fragile X Research, has discovered multiple neurophysiological signatures of FXS, both in the resting state and with sensory, or sound-evoked EEG, that are remarkably conserved between FXS patients and Fmr1 KO mice. Our progress in translational neurophysiology research has benefited greatly from our development of multi- electrode array (MEA) EEG for awake, behaving mice that provides direct parallel to high-density EEG studies in FXS patients. In particular, we discovered EEG biomarkers of enhanced resting state gamma power and impaired auditory chirp-induced cortical synchronization in both Fmr1 KO mice and FXS patients. In the current group of studies, we propose to: (1) define circuit pathophysiology of FXS and develop translational EEG biomarkers; (2) define phenotypic heterogeneity in electrophysiology in female Fmr1 KO and heterozygous mice; and (3) determine effects of target modulation on EEG in Fmr1 KO mice. Both (1) and (3) will be done in coordination with clinicians in Project 1 to evaluate analogous EEG biomarkers across species and test identical drugs. Both (2) and (3) will be done in coordination with Project 3 researchers working on in vitro slice preparations to identify synaptic and cellular deficits. Thus, Project 2 will be a critical hub of the center by translating cellular and molecular level analyses to clinical approaches using network and layer-specific MEA EEG analysis. We anticipate identification of novel biomarker-based drug targets for treatment of FXS. Our approach will serve as a paradigm for drug discovery in neurodevelopmental disorders.