Ferraguto, C.; Bouleau, Y.; Peineau, T.; Dulon, D.; Pietropaolo, S. Hyperacusis in the Adult Fmr1-KO Mouse Model of Fragile X Syndrome: The Therapeutic Relevance of Cochlear Alterations and BKCa Channels. Int. J. Mol. Sci.2023, 24, 11863.
Ferraguto, C.; Bouleau, Y.; Peineau, T.; Dulon, D.; Pietropaolo, S. Hyperacusis in the Adult Fmr1-KO Mouse Model of Fragile X Syndrome: The Therapeutic Relevance of Cochlear Alterations and BKCa Channels. Int. J. Mol. Sci. 2023, 24, 11863.
Ferraguto, C.; Bouleau, Y.; Peineau, T.; Dulon, D.; Pietropaolo, S. Hyperacusis in the Adult Fmr1-KO Mouse Model of Fragile X Syndrome: The Therapeutic Relevance of Cochlear Alterations and BKCa Channels. Int. J. Mol. Sci.2023, 24, 11863.
Ferraguto, C.; Bouleau, Y.; Peineau, T.; Dulon, D.; Pietropaolo, S. Hyperacusis in the Adult Fmr1-KO Mouse Model of Fragile X Syndrome: The Therapeutic Relevance of Cochlear Alterations and BKCa Channels. Int. J. Mol. Sci. 2023, 24, 11863.
Abstract
Hyperacusis, i.e., an increased sensitivity to sounds, is described in several neurodevelopmental disorders (NDDs), including Fragile X Syndrome (FXS). The mechanisms underlying hyperacusis in FXS are still largely unknown and effective therapies are lacking. Big conductance calci-um-activated potassium (BKCa) channels have been proposed as a therapeutic target to treat several behavioral disturbances in FXS preclinical models, but their role in mediating their au-ditory alterations has not been specifically addressed. Furthermore, studies on the acoustic phe-notypes of FXS animal models have mostly focused on central rather than peripheral auditory pathways. Here we provided an extensive characterization of the peripheral auditory phenotype of the Fmr1-knockout (KO) mouse model of FXS at adulthood. We also assessed whether the acute administration of Chlorzoxazone, a BKCa agonist, could rescue the auditory abnormalities of mutant mice. Fmr1-KO mice both at 3 and 6 months showed a hyperacusis-like startle pheno-type with paradoxically reduced auditory brainstem responses associated with a loss of ribbon synapses in the inner hair cells (IHCs). BKCa expression was markedly reduced in the IHCs of KO mice, but only at 6 months, when Chlorzoxazone rescued mutant auditory dysfunction. Our findings highlight the age-dependent and progressive contribution of peripheral mechanisms and BKCa channels to hyperacusis in FXS, suggesting a novel therapeutic target to treat auditory dysfunction in NDDs.
Biology and Life Sciences, Neuroscience and Neurology
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