Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule
Orphanet J Rare Dis. 2014-08-01; 9(1):
DOI: 10.1186/s13023-014-0124-6
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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.