Fragile X syndrome

New Clues to Sound Localization Issues in Fragile X Syndrome

By Pranav Parikh, Kathleen Wallace, and Elizabeth McCullagh, Ph.D.

Fragile X syndrome (FXS), the most common genetic form of autism, is characterized by impaired cognition, hyperactivity, seizures, attention deficits, and hypersensitivity to sensory stimuli, specifically auditory stimuli.

Individuals with FXS also experience difficulty with determining the source of a sound, known as sound localization. Sound localization is essential for listening in the presence of background noise such as a noisy classroom. The ability to localize sound properly is due to precise excitatory and inhibitory inputs to areas of the brain. 2016 Emerging Research Grants recipient Elizabeth McCullagh, Ph.D., and colleagues hypothesize that the auditory symptoms seen in FXS, specifically issues with sound localization, are due to an overall imbalance of excitatory and inhibitory synaptic input in these brain areas.

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Investigators compared number and size of synaptic structures in different areas of the brainstem responsible for sound localization for several inhibitory neurotransmitters (glycine and GABA) and the primary excitatory neurotransmitter (glutamate) in a mouse model of FXS with a control group. The areas of the brainstem responsible for sound localization are connected to one another in a frequency-specific manner, with low frequency sounds stimulating similar areas and the same for high frequency. It was found that most areas of the brainstem examined did not have changes in number or size of structures, but one area—the medial nucleus of the trapezoid body (MNTB)—had alterations to inhibitory inputs that were specific to the frequency encoded by that region. Glycinergic inhibition was decreased in the high frequency region of MNTB, while GABAergic inhibition was decreased in the low frequency region.

The study by McCullagh and team in The Journal of Comparative Neurology is the first to explore alterations in glycinergic inhibition in the auditory brainstem of FXS mice. Due to the well-characterized functional roles of excitatory and inhibitory neurotransmitters in the auditory brainstem, the sound localization pathway is an ideal circuit to measure the sensory alterations of FXS. Given the findings in this study, further knowledge of the alterations in the lower auditory areas, such as the tonotopic differences in inhibition to the MNTB, may be necessary to better understand the altered sound processing found in those with FXS.

Elizabeth McCullagh, Ph.D., was a 2016 Emerging Research Grants scientist and a General Grand Chapter Royal Arch Masons International award recipient. For more, see Tonotopic alterations in inhibitory input to the medial nucleus of the trapezoid body in a mouse model of Fragile X syndrome” in The Journal of Comparative Neurology.

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