Characterization of Auditory and Binaural Spatial Hearing in a Fragile X Syndrome Mouse Model

Abstract

The auditory brainstem compares sound-evoked excitation and inhibition from both ears to compute sound source location and determine spatial acuity. Although alterations to the anatomy and physiology of the auditory brainstem have been demonstrated in fragile X syndrome (FXS), it is not known whether these changes cause spatial acuity deficits in FXS. To test the hypothesis that FXS-related alterations to brainstem circuits impair spatial hearing abilities, a reflexive prepulse inhibition (PPI) task, with variations in sound (gap, location, masking) as the prepulse stimulus, was used on Fmr1 knock-out mice and B6 controls. Specifically, Fmr1 mice show decreased PPI compared with wild-type mice during gap detection, changes in sound source location, and spatial release from masking with no alteration to their overall startle thresholds compared with wild-type mice. Last, Fmr1 mice have increased latency to respond in these tasks, suggesting additional impairments in the pathway responsible for reacting to a startling sound. This study further supports data in humans with FXS that show similar deficits in PPI.

Mechanisms underlying auditory processing deficits in Fragile X syndrome

“…130,[134][135][136][137][138][139][140][141][142][143][144][145] Other studies reported unaltered, enhanced ASR, or reduced PPI. 134,138,139,142 Potential contributors to these discrepancies include, but are not limited to, the genetic background, 140,146 sex (147; but also see137), age, 145 and the sound level for triggering ASR. 140 Particularly, strainspecific differences have been reported in a variety of behavioral phenotypes following Fmr1 deletion 142 and it is known that different mouse strains exhibit varying degrees of ASR in wild-type mouse strains.…”

“…Interestingly, studies of Fmr1 knockout mice show mixed results, perhaps because of the very different hearing range of humans and mice. Many studies found reduced ASR to startle sounds at the level of 90‐120 dB, along with enhanced PPI, as compared to age‐matched wild‐type mice . Other studies reported unaltered, enhanced ASR, or reduced PPI .…”

“…Many studies found reduced ASR to startle sounds at the level of 90‐120 dB, along with enhanced PPI, as compared to age‐matched wild‐type mice . Other studies reported unaltered, enhanced ASR, or reduced PPI . Potential contributors to these discrepancies include, but are not limited to, the genetic background, sex (147; but also see137), age, and the sound level for triggering ASR .…”

Myelination deficits in the auditory brainstem of a mouse model of Fragile X Syndrome, a possible mechanism for auditory phenotypes

“…Additionally, research has shown FMRP expression in mature oligodendrocytes (OLs), potentially explaining how loss of FMRP impacts myelination (Wang et al, 2004;Giampetruzzi et al, 2013). The mechanisms by which binaural hearing is impaired in people with FXS and ASD are unknown, however there is evidence the auditory brainstem is involved (Kulesza and Mangunay, 2008;Kulesza Jr. et al, 2011;Wang et al, 2014;Rotschafer et al, 2015;Garcia-Pino et al, 2017;McCullagh et al, 2017McCullagh et al, , 2020aZorio et al, 2017;Curry et al, 2018;El-Hassar et al, 2019;Lu, 2019).…”

“…Any alteration in this pathway that changes the precision and timing of this circuit will lead to substantial difficulties in the ability to separate competing auditory streams and localize sound, as occurs in ASD. Interestingly, increased changes to latency for both behavioral and physiological measures seem to be one of the more repeatable phenotypes in FXS mice (Kim et al, 2013a;McCullagh et al, 2020a, but see Rotschafer et al, 2015El-Hassar et al, 2019). One way in which changes to myelination in the auditory brainstem would likely manifest is through changes in the speed of synaptic transmission, and therefore latency of auditory brainstem timing.…”