Mechanisms and Biomarkers of Sensory Hypersensitivity in the fmr1 Knockout Mouse

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.

Devin Binder is currently Professor in the Division of Biomedical Sciences in the School of Medicine at the University of California, Riverside. His research has focused in several areas:

1. Astrocytes and epilepsy. The Binder laboratory has discovered significant changes in key astrocyte molecules, notably aquaporin-4 (AQP4) and glutamate transporter-1 (GLT1) in animal models of epilepsy. Current research is aimed at understanding these astrocytic contributions to epileptogenesis and developing astrocyte-targeted therapeutic approaches.
2. Development of imaging and biomedical engineering approaches to brain and spinal cord edema. Together with bioengineering collaborators, the Binder laboratory has developed new methods for early diagnosis and treatment of brain and spinal cord edema after injury.
3. Development and application of novel neurophysiological techniques. The Binder laboratory has recently developed multielectrode array (MEA) technology for application to physiological studies of Fragile X syndrome (FXS) mutant mice and to localize the onset of epilepsy after brain trauma (posttraumatic epilepsy).

Khaleel Razak is an auditory neurophysiologist whose long-term research goals are to understand how the auditory system represents everyday sounds, and how such representation changes during development, aging and syndromes with communication implications such as FXS. He received his PhD in 2001 at the University of Wyoming and joined the faculty at UC, Riverside in 2007. He is a Professor in the Department of Psychology.