Neural Correlates of Auditory Hypersensitivity in Fragile X Syndrome

Abstract

The mechanisms underlying the common association between autism spectrum disorders (ASD) and sensory processing disorders (SPD) are unclear, and treatment options to reduce atypical sensory processing are limited. Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and ASD behaviors. As in most children with ASD, atypical sensory processing is a common symptom in FXS, frequently manifesting as sensory hypersensitivity. Auditory hypersensitivity is a highly debilitating condition in FXS that may lead to language delays, social anxiety and ritualized repetitive behaviors. Animal models of FXS, including Fmr1 knock out (KO) mouse, also show auditory hypersensitivity, providing a translation relevant platform to study underlying pathophysiological mechanisms. The focus of this review is to summarize recent studies in the Fmr1 KO mouse that identified neural correlates of auditory hypersensitivity. We review results of electroencephalography (EEG) recordings in the Fmr1 KO mice and highlight EEG phenotypes that are remarkably similar to EEG findings in humans with FXS. The EEG phenotypes associated with the loss of FMRP include enhanced resting EEG gamma band power, reduced cross frequency coupling, reduced sound-evoked synchrony of neural responses at gamma band frequencies, increased event-related potential amplitudes, reduced habituation of neural responses and increased non-phase locked power. In addition, we highlight the postnatal period when the EEG phenotypes develop and show a strong association of the phenotypes with enhanced matrix-metalloproteinase-9 (MMP-9) activity, abnormal development of parvalbumin (PV)-expressing inhibitory interneurons and reduced formation of specialized extracellular matrix structures called perineuronal nets (PNNs). Finally, we discuss how dysfunctions of inhibitory PV interneurons may contribute to cortical hyperexcitability and EEG abnormalities observed in FXS. Taken together, the studies reviewed here indicate that EEG recordings can be utilized in both pre-clinical studies and clinical trials, while at the same time, used to identify cellular and circuit mechanisms of dysfunction in FXS. New therapeutic approaches that reduce MMP-9 activity and restore functions of PV interneurons may succeed in reducing FXS sensory symptoms. Future studies should examine long-lasting benefits of developmental vs. adult interventions on sensory phenotypes.

FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT1A, 5-HT1B, and 5-HT1D Receptor Agonist That Modulates Cortical Electroencephalogram Activity in Adult Fmr1 Knockout Mice

“…We observed an increase in relative gamma (30–100 Hz) power measured above the left somatosensory cortex in adult female Fmr1 KO mice, compared to WT mice during baseline recordings; we also observed this effect in female and male Fmr1 KO mice in the vehicle treatment group condition. The high relative gamma-band power in male Fmr1 KO was like what others have reported . Considering sex effects, female Fmr1 KO exhibited higher relative gamma power at baseline and after vehicle injection than male Fmr1 KO mice.…”

“…The high relative gamma-band power in male Fmr1 KO was like what others have reported. 39 Considering sex effects, female Fmr1 KO exhibited higher relative gamma power at baseline and after vehicle injection than male Fmr1 KO mice. Most EEG studies report that males but not females�humans with FXS and Fmr1 KO mice�show increased gamma power, 18,37 though there are notable exceptions wherein researchers have not observed an increase in cortical gamma power in male Fmr1 KO mice and rats.…”

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

“…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 ). Clinically, auditory phenotypes present as reduced auditory attention, impaired habituation to auditory stimuli, reduced prepulse inhibition of acoustic startle, and overall hypersensitivity to auditory conditions (reviewed in Sinclair et al, 2017 ; Rais et al, 2018 ; Razak et al, 2021 ) that have likely both cortical and subcortical origins. Indeed, much of the research in this area has focused on cortical measures of auditory phenotypes, which receive inputs from lower auditory regions that may also be disrupted but less likely to be measured clinically.…”

Astrocytes regulate inhibition in Fragile X Syndrome

“…We used a multidisciplinary approach including transcriptional, cellular, molecular, electrophysiological, and behavioral methods to delineate the astrocyte-mediated mechanisms of abnormal inhibition in FXS. We utilized both human and mouse astrocytes, and the analysis of translationally relevant electroencephalogram (EEG) phenotypes that are remarkably similar between the mouse model of FXS and the human condition across different brain areas implicated in FXS-associated behaviors 36 . Interestingly, specific deletion of Fmr1 from astrocytes resulted in more severe deficits than the effects of Fmr1 deletion from PC 14, 37 .…”