FRAXA Webinar Series
This virtual seminar series addresses a wide range of current topics in Fragile X research. Hosted by FRAXA and organized by Michael Tranfaglia, MD, this series features outstanding speakers from universities and the biotech and pharmaceutical industries.
Presentation Abstract
Sensory hypersensitivity is a common and debilitating symptom of Fragile X syndrome (FXS) and may underlie developmental delays and high anxiety. This is particularly prevalent in the auditory modality with both humans with FXS and the mouse model (fmr1 KO mouse) showing behavioral disruptions due to presence of constant and/or unpredictable sounds. Low level auditory processing circuits are likely more conserved across species compared to those involved in social and cognitive functions. There is also a rich history of studying the development of audition in both humans and animals. Together, this provides strong justification for studying mechanisms and biomarkers of auditory processing to facilitate the pre-clinical to clinical pipeline, while generating circuit level understanding of pathophysiology and development of FXS.
Over the past 10 years, we have studied the auditory system of the fmr1 KO mice and identified a ‘quadruple-hit’ model for hypersensitivity. Using in vivo single neuron and EEG recordings, we have found that the fmr1 KO (compared to WT) mouse cortical neurons show increased responses to individual sounds even well after sound offset, reduced habituation to ongoing sounds, increased background noise in the gamma frequency band and reduced temporal fidelity. These correlates are remarkably similar to those found by others in humans with FXS. We have also identified that abnormal sensitivity develops between post-natal day (P)14 – P21 in the mouse due to a mechanism that depends on elevated matrix-metalloproteinase-9 (MMP-9). Treatment of mice with inhibitors of MMP-9 reduces the phenotypes of the quadruple hit model. To further increase translational relevance of our approach, we have now developed a 30-channel multi-electrode array (MEA)-based skull EEG recording system. Using this system, we have quantified EEG responses across multiple sites in the skull and have identified regional differences in phenotypes and response to candidate drug treatments. This system may serve as a translational platform for drug development in FXS.
Our work is supported by FRAXA, NIH and DOD.
About the Speaker(s)
Xinyu Zhao, PhD
Jenni and Kyle Professor
Waisman Center and Department of Neuroscience
University of Wisconsin-Madison
Dr. Xinyu Zhao graduated from Peking (Beijing) University with a BS degree in Biology and then earned her PhD degree in Pharmacology from the University of Washington (Seattle). She then obtained postdoctoral training from Dr. Fred Gage at the Salk Institute for Biological Studies (La Jolla, California). Dr. Zhao started her own independent research at the University of New Mexico School of Medicine in 2003 and then moved to the University of Wisconsin-Madison in 2011. She is currently a Jeni and Kyle Professor in the Department of Neuroscience and an investigator of the Waisman Center. Dr. Zhao’s research focuses on understanding the molecular mechanisms that regulate brain development with the goal of developing novel treatment strategies for neurodevelopmental disorders.