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GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Behavioral Deficits in the Fmr1 Knockout Mouse Model of Fragile X Syndrome

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Sinclair, D ORCID: 0000-0001-5961-1007, Featherstone, R, Naschek, M, Nam, J, Du, A, Wright, S, Pance, K, Melnychenko, O, Weger, R, Akuzawa, S, Matsumoto, M and Siegel, SJ 2017 , 'GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Behavioral Deficits in the Fmr1 Knockout Mouse Model of Fragile X Syndrome' , eNeuro, vol. 4, no. 1 , pp. 1-13 , doi: 10.1523/ENEURO.0380-16.2017.

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Abstract

Fragile X syndrome is a genetic condition resulting from FMR1 gene mutation that leads to intellectual disability, autism-like symptoms, and sensory hypersensitivity. Arbaclofen, a GABA-B agonist, has shown efficacy in some individuals with FXS but has become unavailable after unsuccessful clinical trials, prompting interest in publicly available, racemic baclofen. The present study investigated whether racemic baclofen can remediate abnormalities of neural circuit function, sensory processing, and behavior in Fmr1 knockout mice, a rodent model of fragile X syndrome. Fmr1 knockout mice showed increased baseline and auditory-evoked high-frequency gamma (30–80 Hz) power relative to C57BL/6 controls, as measured by electroencephalography. These deficits were accompanied by decreased T maze spontaneous alternation, decreased social interactions, and increased open field center time, suggestive of diminished working memory, sociability, and anxiety-like behavior, respectively. Abnormal auditory-evoked gamma oscillations, working memory, and anxiety-related behavior were normalized by treatment with baclofen, but impaired sociability was not. Improvements in working memory were evident predominantly in mice whose auditory-evoked gamma oscillations were dampened by baclofen. These findings suggest that racemic baclofen may be useful for targeting sensory and cognitive disturbances in fragile X syndrome.

Item Type: Article
Authors/Creators:Sinclair, D and Featherstone, R and Naschek, M and Nam, J and Du, A and Wright, S and Pance, K and Melnychenko, O and Weger, R and Akuzawa, S and Matsumoto, M and Siegel, SJ
Keywords: EEG; fragile X syndrome; GABA; gamma; racemic baclofen; working memory
Journal or Publication Title: eNeuro
Publisher: Society for Neuroscience
ISSN: 2373-2822
DOI / ID Number: 10.1523/ENEURO.0380-16.2017
Copyright Information:

Copyright © 2017 by the Society for Neuroscience

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