Auditory hypersensitivity and processing deficits in a rat model of fragile X syndrome

AbstractMany people affected by fragile X syndrome (FXS) and autism spectrum disorders have sensory processing deficits, such as hypersensitivity to auditory, tactile, and visual stimuli. Like FXS in humans, loss of Fmr1 in rodents also cause sensory, behavioral, and cognitive deficits. However, the neural mechanisms underlying sensory impairment, especially vision impairment, remain unclear. It remains elusive whether the visual processing deficits originate from corrupted inputs, impaired perception in the primary sensory cortex, or altered integration in the higher cortex, and there is no effective treatment. In this study, we used a genetic knockout mouse model (Fmr1KO), in vivo imaging, and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex (V1). Specifically, Fmr1KO mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli. This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons. These effects were ameliorated by the acute application of GABAA receptor activators, which enhanced the activity of inhibitory neurons, or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice. Overall, V1 plays an important role in the visual abnormalities of Fmr1KO mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.

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Correction of amygdalar dysfunction in a rat model of fragile X syndrome

Cell Reports ◽

10.1016/j.celrep.2021.109805 ◽

2021 ◽

Vol 37 (2) ◽

pp. 109805

Author(s):

Giselle Fernandes ◽

Pradeep K. Mishra ◽

Mohammad Sarfaraz Nawaz ◽

Paul G. Donlin-Asp ◽

Mohammed Mostafizur Rahman ◽

...

Keyword(s):

Fragile X Syndrome ◽

Rat Model ◽

Fragile X

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Sensory hypo-excitability in a rat model of fetal development in Fragile X Syndrome

Scientific Reports ◽

10.1038/srep30769 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 22

Author(s):

Julia Berzhanskaya ◽

Marnie A. Phillips ◽

Jing Shen ◽

Matthew T. Colonnese

Keyword(s):

Fragile X Syndrome ◽

Rat Model ◽

Fragile X ◽

Gamma Oscillations ◽

Developmental Trajectory ◽

Inhibitory Neurons ◽

Visual Responses ◽

Age Appropriate ◽

Eye Opening ◽

Hyper Sensitivity

Abstract Fragile X syndrome (FXS) is characterized by sensory hyper-sensitivity, and animal models suggest that neuronal hyper-excitability contributes to this phenotype. To understand how sensory dysfunction develops in FXS, we used the rat model (FMR-KO) to quantify the maturation of cortical visual responses from the onset of responsiveness prior to eye-opening, through age equivalents of human juveniles. Rather than hyper-excitability, visual responses before eye-opening had reduced spike rates and an absence of early gamma oscillations, a marker for normal thalamic function at this age. Despite early hypo-excitability, the developmental trajectory of visual responses in FMR-KO rats was normal, and showed the expected loss of visually evoked bursting at the same age as wild-type, two days before eye-opening. At later ages, during the third and fourth post-natal weeks, signs of mild hyper-excitability emerged. These included an increase in the visually-evoked firing of regular spiking, presumptive excitatory, neurons, and a reduced firing of fast-spiking, presumptive inhibitory, neurons. Our results show that early network changes in the FMR-KO rat arise at ages equivalent to fetal humans and have consequences for excitability that are opposite those found in adults. This suggests identification and treatment should begin early, and be tailored in an age-appropriate manner.

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Gene Therapy Using an Orthologue of Human Fragile X Mental Retardation Protein Partially Rescues Behavioural Abnormalities and EEG Activity in a Rat Model of Fragile X Syndrome

Molecular Therapy — Methods & Clinical Development ◽

10.1016/j.omtm.2021.06.013 ◽

2021 ◽

Author(s):

Alexander W.M. Hooper ◽

Hayes Wong ◽

Yosuke Niibori ◽

Rozita Abdoli ◽

Subha Karumuthil-Melethil ◽

...

Keyword(s):

Gene Therapy ◽

Mental Retardation ◽

Fragile X Syndrome ◽

Rat Model ◽

Fragile X ◽

Eeg Activity ◽

Fragile X Mental Retardation ◽

Mental Retardation Protein

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Auditory Hypersensitivity and Processing Deficits in a Rat Model of Fragile X Syndrome

10.1101/2021.09.25.461569 ◽

2021 ◽

Author(s):

Benjamin D Auerbach ◽

Senthilvelan Manohar ◽

Kelly Radziwon ◽

Richard Salvi

Keyword(s):

Auditory System ◽

Rat Model ◽

Auditory Processing ◽

Fragile X ◽

Autism Spectrum ◽

Sound Perception ◽

Sensory Hypersensitivity ◽

Spectral Integration ◽

Processing Deficits ◽

Loudness Growth

Fragile X (FX) syndrome is one of the leading inherited causes of autism spectrum disorder (ASD). A majority of FX and ASD patients exhibit sensory hypersensitivity, including auditory hypersensitivity or hyperacusis, a condition in which everyday sounds are perceived as much louder than normal. Auditory processing deficits in FX and ASD also afford the opportunity to develop objective and quantifiable outcome measures that are likely to translate between humans and animal models due to the well-conserved nature of the auditory system and well-developed behavioral read-outs of sound perception. Therefore, in this study we characterized auditory hypersensitivity in a Fmr1 knockout (KO) transgenic rat model of FX using an operant conditioning task to assess sound detection thresholds and suprathreshold auditory reaction time-intensity (RT-I) functions, a reliable psychoacoustic measure of loudness growth, at a variety of stimulus frequencies, bandwidths and durations. Male Fmr1 KO and littermate WT rats both learned the task at the same rate and exhibited normal hearing thresholds. However, Fmr1 KO rats had faster auditory RTs over a broad range of intensities and steeper RT-I slopes than WT controls, perceptual evidence of excessive loudness growth in Fmr1 KO rats. Furthermore, we found that Fmr1 KO animals exhibited abnormal perceptual integration of sound duration and bandwidth, with diminished temporal but enhanced spectral integration of sound intensity. Because temporal and spectral integration of sound stimuli were altered in opposite directions in Fmr1 KO rats, this suggests that abnormal RTs in these animals are evidence of aberrant auditory processing rather than generalized hyperactivity or altered motor responses. Together, these results are indicative of fundamental changes to low-level auditory processing in Fmr1 KO animals. Finally, we demonstrated that antagonism of metabotropic glutamate receptor 5 (mGlu5) selectively and dose-dependently restored normal loudness growth in Fmr1 KO rats, suggesting a pharmacologic approach for alleviating sensory hypersensitivity associated with FX. This study leverages the tractable nature of the auditory system and the unique behavioral advantages of rats to provide important insights into the nature of a centrally important yet understudied aspect of FX and ASD.

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