부산대학교 도서관

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 [mu]M) 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. Keywords: Fragile X Syndrome, BMS-204352, BKCa channel, Sociability, Cognition, Anxiety
Author(s): Betty Hñbert[sup.1,2] , Susanna Pietropaolo[sup.3,4] , Sandra Même[sup.5] , Bñatrice Laudier[sup.1,2,6] , Anthony Laugeray[sup.1,2] , Nicolas Doisne[sup.1,2] , Angñlique Quartier[sup.1,2] , Sandrine Lefeuvre[sup.6] , Laurence Got[sup.6] , Dominique Cahard[sup.7] [...]