Abstract
In fragile X syndrome (FXS), sensory hypersensitivity and impaired habituation is thought to result in attention overload and various behavioral abnormalities in reaction to the excessive and remanent salience of environment features that would normally be ignored. This phenomenon, termed sensory defensiveness, has been proposed as the potential cause of hyperactivity, hyperarousal, and negative reactions to changes in routine that are often deleterious for FXS patients. However, the lack of tools for manipulating sensory hypersensitivity has not allowed the experimental testing required to evaluate the relevance of this hypothesis. Recent work has shown that BMS-204352, a BKCa channel agonist, was efficient to reverse cortical hyperexcitability and related sensory hypersensitivity in the Fmr1-KO mouse model of FXS. In the present study, we report that exposing Fmr1-KO mice to novel or unfamiliar environments resulted in multiple behavioral perturbations, such as hyperactivity, impaired nest building and excessive grooming of the back. Reversing sensory hypersensitivity with the BKCa channel agonist BMS-204352 prevented these behavioral abnormalities in Fmr1-KO mice. These results are in support of the sensory defensiveness hypothesis, and confirm BKCa as a potentially relevant molecular target for the development of drug medication against FXS/ASD.
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Acknowledgements
We thank Nora Abrous and Guillaume Lucas for feedback on the manuscript. This work was supported by funding from INSERM, CNRS, and Agence Nationale pour la Recherche (ANR). We thank the Animal Housing and Genotyping facilities, supported by funding from INSERM and LabEX BRAIN (ANR-10-LABX-43). MICM was supported by an international PhD fellowship (ANR-10-IDEX-03-02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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XL conceived the project. MICM, MG, AF, and XL planned the research. MICM, FM, MCM, EA, CD, ES, GB, MG, and XL performed data acquisition. MICM, FM, EA, CD, SP, GB, AM, and XL analyzed the data. MICM and XL wrote the paper and all other authors provided feedback.
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Carreno-Munoz, M., Martins, F., Medrano, M. et al. Potential Involvement of Impaired BKCa Channel Function in Sensory Defensiveness and Some Behavioral Disturbances Induced by Unfamiliar Environment in a Mouse Model of Fragile X Syndrome. Neuropsychopharmacol. 43, 492–502 (2018). https://doi.org/10.1038/npp.2017.149
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DOI: https://doi.org/10.1038/npp.2017.149
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