Project 2: Wilkerson

PROJECT 2 – PROJECT SUMMARY Autism spectrum disorder (ASD) occurs in 1 in 54 US children and often features hearing impairments such as hyperacusis, auditory processing disorders and sensorineural hearing loss, along with difficulties in social communication. The Center of Biomedical Research Excellence in Neurodevelopment and its Disorders (CNDD) supports the cross-cutting, innovative research needed to advance fundamental understanding of the unique hearing impairments and pathophysiology of the auditory system in ASD and their role in social communication. This research studies the role of the peripheral auditory system in the development of hearing impairments and ASD-like behaviors in a mouse model of Fragile X Syndrome (FXS), the most common monogenetic type of ASD. We hypothesize that hearing impairments in FXS are due in part to defects in the cochlea and to dysfunction in both neuronal and non-neuronal Fmr1-expressing cells including sensory hair cells, but also other nonsensory cells in the inner ear. Aim 1 tests methods to rescue hearing function and mitigate related ASD-like behaviors in the developing Fmr1 knockout (KO) mouse and Aim 2 investigates the pathophysiological changes in cellular composition and cell type-specific gene expression patterns in the Fmr1 KO cochlea by single nucleus RNA-seq (snRNA-seq). Our findings could provide (1) new evidence about the role of peripheral sensory deficits in ASD-related symptoms, (2) critical new insights into the role of neuronal vs. non-neuronal FMRP functions in cochlear development and auditory function and (3) test a gene therapeutic approach to possibly rescue auditory function and/or reduce communication-related symptoms of ASD. To understand how gene networks in the peripheral auditory system are deregulated in ASD, this research uses omics approaches for systematic mapping of complex genetic networks. Study of the fundamental processes that contribute to hearing differences in ASD could identify therapeutic strategies to resolve hearing differences and related language and social communication challenges. Critical components of the CNDD for this project are cores for neurobehavioral phenotyping, in vivo imaging, and bioinformatics, advanced biostatistical consulting, and also significant resources for research capacity and training including career development mentorship and tools for advancement to independence and success in obtaining R01-level funding to continue research in the pathophysiology of the auditory system in ASD.