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BioMed Central, Orphanet Journal of Rare Diseases, 1(9), 2014

DOI: 10.1186/s13023-014-0124-6

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Rescue of fragile X syndrome phenotypes in Fmr1KO mice by a BKCa channel opener molecule

Journal article published in 2014 by Betty Hébert, Susanna Pietropaolo ORCID, Sandra Même, Béatrice Laudier, Anthony Laugeray, Nicolas Doisne ORCID, Angélique Quartier ORCID, Sandrine Lefeuvre, Laurence Got, Dominique Cahard, Frédéric Laumonnier ORCID, Wim E. Crusio, Jacques Pichon, Arnaud Menuet, Olivier Perche and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

Abstract Background Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and is also associated with autism spectrum disorders. Previous studies implicated BKCa channels in the neuropathogenesis of FXS, but the main question was whether pharmacological BKCa stimulation would be able to rescue FXS neurobehavioral phenotypes. Methods and results We used a selective BKCa channel opener molecule (BMS-204352) to address this issue in Fmr1 KO mice, modeling the FXS pathophysiology. In vitro , acute BMS-204352 treatment (10 μM) restored the abnormal dendritic spine phenotype. In vivo, a single injection of BMS-204352 (2 mg/kg) rescued the hippocampal glutamate homeostasis and the behavioral phenotype. Indeed, disturbances in social recognition and interaction, non-social anxiety, and spatial memory were corrected by BMS-204352 in Fmr1 KO mice. Conclusion These results demonstrate that the BKCa channel is a new therapeutic target for FXS. We show that BMS-204352 rescues a broad spectrum of behavioral impairments (social, emotional and cognitive) in an animal model of FXS. This pharmacological molecule might open new ways for FXS therapy.