Characterization of auditory physiology in FXS mice at critical developmental timepoints

Abstract

Autism spectrum disorders are strongly associated with auditory hypersensitivity. Fragile X syndrome (FXS), a common monogenic cause of ASD, results from transcriptional silencing of the Fmr1 gene and reduced expression of fragile X messenger ribonucleo-protein (FMRP). FMRP directly impacts myelin proteins and various brain regions show reduced/delayed myelination in FXS, suggesting deficits seen in FXS may be caused by alterations to myelination. FXS is a neurodevelopmental disorder, therefore characterizing when during development auditory dysfunction arises in addition to understanding if these changes are myelin dependent is critical to elucidating the full etiology of FXS.Auditory brainstem response (ABR) measurements record 1-4 waves, each corresponding to part of the ascending auditory pathway; the latency of which could be directly related to myelination of auditory areas. To characterize the physiology of myelination deficits in FXS at developmental time points, ABR measurements were taken for transgenic Fmr1 mice and controls before (P8-10), during (P12-14) or after (P21-23 and adult) hearing onset in mice. This allowed us to study the developmental emergence of auditory disruptions in Fmr1 transgenic mice and identify critical windows where underlying auditory pathways are established. We hypothesize that transgenic Fmr1 mice will have ncreased latencies and decreased amplitudes in their ABR waves compared to the wildtype at different developmental time points. These data will aid in identifying the critical developmental windows of neural circuitry establishment in auditory sensory systems and potential myelination impairments that underly auditory dysfunction observed in patients and mice with FXS.