Over the last six years our project teams have demonstrated that neurophysiology abnormalities are conserved across mice and humans in fragile X syndrome (FXS). These findings across species provide a great opportunity to advance mechanistic understanding of clinically relevant illness features and develop translational biomarkers and aid treatment discovery. These advances can bridge the significant chasm between preclinical and clinical success in new treatment development. We take mechanistic approaches to determining the drivers of neurophysiology dysregulation across three integrated projects spanning human, in vivo, and ex vivo mouse study. This allows for levels of analysis from whole brain network modeling to microcircuit and molecular analysis to aid target discovery while improving translational medicine efforts in FXS. In doing this we place emphasis on recognizing heterogeneity within FXS and using this understanding to model how to best interpret and link preclinical and clinical study. Out of this appreciation of the challenges to translational efforts in our field, we have developed a synchronized approach to the analysis and interpretation of neurophysiology data ensuring comparable results across research platforms. The striking consistency of findings across levels of investigation and species offers an unprecedented opportunity to investigate mechanisms of brain dysfunction across mouse and human study thus significantly improving opportunities for translational medicine development in FXS- a multidisciplinary mission that is ideal for a Center environment. Project 1 (Erickson/Sweeney; Cincinnati) will conduct human FXS neurophysiology, behavior, and pharmacological probe studies to pursue advanced neurophysiology modeling of cortical hyperexcitability and abnormal response to stimuli while also seeking to resolve heterogeneity across FXS in humans. Project 2 (Binder/Razak; Riverside) will develop translational neurophysiological biomarkers for FXS in the Fmr1 KO mouse using both surface and depth multi-electrode array technology. Project 3 (Huber/Gibson, UTSW) will investigate the microcircuit and molecular mechanisms of neurophysiologic dysregulation in the Fmr1 KO mouse. All Projects will examine candidate mechanisms of neurophysiologic dysregulation with a pharmacological probe strategy to test mechanisms of interest in parallel studies of mice and patients.
The overarching goal of our Center proposal entitled ?Translational Medicine and Mechanistic Studies of Brain Neurophysiology in Fragile X Syndrome? is to utilize highly interrelated research strategies with two primary aims, advancing translational medicine approaches (biomarker development, drug challenge studies, resolving illness heterogeneity) and expanding the mechanistic understanding of Fragile X syndrome (FXS) biology. The goal of this work is to foster the development of new, more effective therapies. We propose to pursue these aims through the establishment of integrated, interdependent research programs from patient-centered research to in vivo animal experiments to cellular sub-type specific and molecular models.
