Auditory Brain Stem Responses in the C57BL/6J Fragile X Syndrome-Knockout Mouse Model.

Amita Chawla,Elizabeth A Mccullagh

doi:10.3389/fnint.2021.803483

Amita Chawla, Elizabeth A Mccullagh

Open Access

https://doi.org/10.3389/fnint.2021.803483

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Abstract

Sensory hypersensitivity, especially in the auditory system, is a common symptom in Fragile X syndrome (FXS), the most common monogenic form of intellectual disability. However, linking phenotypes across genetic background strains of mouse models has been a challenge and could underly some of the issues with translatability of drug studies to the human condition. This study is the first to characterize the auditory brain stem response (ABR), a minimally invasive physiological readout of early auditory processing that is also used in humans, in a commonly used mouse background strain model of FXS, C57BL/6J. We measured morphological features of pinna and head and used ABR to measure the hearing range, and monaural and binaural auditory responses in hemizygous males, homozygous females, and heterozygous females compared with those in wild-type mice. Consistent with previous study, we showed no difference in morphological parameters across genotypes or sexes. There was no significant difference in hearing range between the sexes or genotypes, however there was a trend towards high frequency hearing loss in male FXS mice. In contrast, female mice with homozygous FXS had a decreased amplitude of wave IV of the monaural ABR, while there was no difference in males for amplitudes and no change in latency of ABR waveforms across sexes and genotypes. Finally, males with FXS had an increased latency of the binaural interaction component (BIC) at 0 interaural timing difference compared with that in wild-type males. These findings further clarify auditory brain stem processing in FXS by adding more information across genetic background strains allowing for a better understanding of shared phenotypes.

Highlights

Fragile X syndrome (FXS) is the most common monogenic form of autism spectrum disorder (ASD) and shares many attributes of ASDs, including auditory hypersensitivity and other sensory disruptions (Abbeduto and Hagerman, 1997; Chen and Toth, 2001; Hagerman and Hagerman, 2002; Arnett et al, 2014)
We reported on the hearing ability, using the auditory brain stem response (ABR) and morphological craniofacial and pinna features, of the most common mouse model with FXS, C57BL/6J across the sexes and females heterozygous for the Fmr1 mutation
Similar to the pinna morphology, there was no significant difference in either distance between pinna or distance from the nose to pinna between the genotypes or sexes (Figures 1E,F)

Summary

Introduction

Fragile X syndrome (FXS) is the most common monogenic form of autism spectrum disorder (ASD) and shares many attributes of ASDs, including auditory hypersensitivity and other sensory disruptions (Abbeduto and Hagerman, 1997; Chen and Toth, 2001; Hagerman and Hagerman, 2002; Arnett et al, 2014). FXS is a tractable genetic model for ASD with several commercially available models, including the rat and mouse (The Dutch-Belgian Fragile X Consorthium et al, 1994; Till et al, 2015; Tian et al, 2017). One of the most common symptoms described in people with FXS and autism spectrum disorder (ASD) is auditory hypersensitivity (Ethridge et al, 2017; Stefanelli et al, 2020).

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