Abstract

Fragile X syndrome (FXS) is an inherited form of intellectual disability and autism. Among other symptoms, FXS patients demonstrate abnormalities in sensory processing and communication. Clinical, behavioral, and electrophysiological studies consistently show auditory hypersensitivity in humans with FXS. Consistent with observations in humans, the Fmr1 KO mouse model of FXS also shows evidence of altered auditory processing and communication deficiencies. A well-known and commonly used phenotype in pre-clinical studies of FXS is audiogenic seizures. In addition, increased acoustic startle response is seen in the Fmr1 KO mice. In vivo electrophysiological recordings indicate hyper-excitable responses, broader frequency tuning, and abnormal spectrotemporal processing in primary auditory cortex of Fmr1 KO mice. Thus, auditory hyper-excitability is a robust, reliable, and translatable biomarker in Fmr1 KO mice. Abnormal auditory evoked responses have been used as outcome measures to test therapeutics in FXS patients. Given that similarly abnormal responses are present in Fmr1 KO mice suggests that cellular mechanisms can be addressed. Sensory cortical deficits are relatively more tractable from a mechanistic perspective than more complex social behaviors that are typically studied in autism and FXS. The focus of this review is to bring together clinical, functional, and structural studies in humans with electrophysiological and behavioral studies in mice to make the case that auditory hypersensitivity provides a unique opportunity to integrate molecular, cellular, circuit level studies with behavioral outcomes in the search for therapeutics for FXS and other autism spectrum disorders.

Highlights

  • Autism spectrum disorder is a growing concern, affecting 0.7–1% of all children born in the United States (Centers for Disease Control and Prevention, 2009)

  • Consistent with the results in Fragile X syndrome (FXS) patients, Fmr1 knockout mouse (Fmr1 KO) mice exhibit a variety of abnormal responses to auditory stimuli, and provide a means of studying the neural correlates and mechanisms underlying auditory processing symptoms of human FXS

  • The mechanisms underlying sensory hypersensitivity may be relatively more tractable compared to more complex social behaviors typically studied in FXS

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Summary

Auditory processing in fragile X syndrome

FXS patients demonstrate abnormalities in sensory processing and communication. Behavioral, and electrophysiological studies consistently show auditory hypersensitivity in humans with FXS. Consistent with observations in humans, the Fmr KO mouse model of FXS shows evidence of altered auditory processing and communication deficiencies. In vivo electrophysiological recordings indicate hyper-excitable responses, broader frequency tuning, and abnormal spectrotemporal processing in primary auditory cortex of Fmr KO mice. Abnormal auditory evoked responses have been used as outcome measures to test therapeutics in FXS patients. The focus of this review is to bring together clinical, functional, and structural studies in humans with electrophysiological and behavioral studies in mice to make the case that auditory hypersensitivity provides a unique opportunity to integrate molecular, cellular, circuit level studies with behavioral outcomes in the search for therapeutics for FXS and other autism spectrum disorders

INTRODUCTION
Rotschafer and Razak
ERP component Changes in FXS patients
In vivo extracellular electrophysiology
Findings
CONCLUSIONS AND FUTURE STUDIES
Full Text
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