Mechanisms of Auditory Hypersensitivity in Fragile X Syndrome
Abstract
The leading inherited cause of intellectual disability and autism, Fragile X syndrome (FXS), affects 1 in 4,000 boys and 1 in 8,000 girls. Disabilities ranging from mild to severe include behavioral effects such as excitability, hyperactivity, anxiety, abnormal social interactions, and increased sensitivity to sounds. Some of the same symptoms are also present in conditions such as post-traumatic stress disorder that affect military personnel, whose families bear an additional burden from FXS. Because FXS is the result of cells failing to produce a protein called FMRP, research has focused on testing drugs that make up for the absence of this protein in mice that have a similar inherited condition. But beneficial effects of drugs on cognitive behaviors in mice are difficult to compare with cognitive behaviors in people with FXS. There is an immediate need to identify robust and translation-relevant outcome measures in FXS given that two recent clinical trials failed to produce the effects in humans that were predicted based on strong outcomes in mice. Sensory deficits, unlike cognitive deficits, in FXS may provide an opportunity to develop translation-relevant biomarkers. Basic sensory responses, circuits, and plasticity mechanisms are more conserved across animals than complex cognitive behaviors. Identifying circuit level mechanisms underlying FXS pathophysiology may be relatively less daunting for basic sensory deficits and early cortical processing compared to higher-level cognitive functions. Therefore, the proposed experiments uniquely bring together the expertise of an auditory electrophysiologist, a biochemist, a seizure specialist, and a hearing scientist from the Veterans Affairs Healthcare System to investigate the neural mechanisms of auditory cortical developmental plasticity deficits and auditory hypersensitivity. The structural and functional mechanisms identified here will identify novel therapeutic targets for FXS and autism in general. The rationale for studying the auditory system in these experiments arises from the fact that auditory processing and language functions are severely compromised in humans with FXS. Seizures also occur in ~20% of patients compared to 1%-2% of the general population. The mouse model of FXS, the Fmr1 KO mouse, also suffers from abnormal auditory processing, increased acoustic startle response, and seizures triggered by auditory stimuli. The mouse model also exhibits abnormal developmental plasticity, including deficits in auditory experience-dependent plasticity. Early developmental deficits in basic sound processing may lead to higher-level auditory processing including language functions in humans with FXS. However, the underlying mechanisms for any of these deficits remain unknown. The proposed experiments will utilize a broad range of innovative approaches including in vivo neurophysiology, immunohistochemistry, clinically relevant EEG (electroencephalography) studies, and mouse genetics to identify these mechanisms. Discovery of auditory abnormalities and mechanisms in FXS mice has importance for humans, especially when these biomarkers of disease (or its reversal) can be measured and compared. Therefore, identification of mechanisms of sensory deficits in the mouse cortex will lead to translation relevant biomarkers to understand FXS pathophysiology in humans.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510434
Entities
People
- Khaleel Razak
Organizations
- United States Army
- University of California, Riverside