Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule

Orphanet Journal of Rare Diseases

Sylvain Briault⁶  Olivier Perche⁶  Arnaud Menuet⁴  Jacques Pichon⁴  Wim E Crusio²  Frédéric Laumonnier³  Dominique Cahard⁵  Laurence Got⁶  Sandrine Lefeuvre⁶  Angélique Quartier⁴  Nicolas Doisne⁴  Anthony Laugeray⁴  Béatrice Laudier⁶  Sandra Même¹  Susanna Pietropaolo²  Betty Hébert⁴ 

[1]Centre de Biophysique Moléculaire, UPR4301, CNRS, University of Orléans, Rue Charles Sadron, Orléans, 45071, Cedex, France

[2]The Aquitaine Institute for Cognitive and Integrative Neuroscience, University of Bordeaux, Avenue des Facultés, Talence, 33405, France

[3]UMR Imagerie et cerveau, François-Rabelais University, Tours 37000, France

[4]Experimental and Molecular Immunology and Neurogenetics, University of Orléans, 3b rue de la Férollerie, Orléans, 45071, Cedex 2, France

[5]UMR CNRS 6014 C.O.B.R.A., INSA of Rouen, 1 rue Tesnière, Mont Saint Aignan, 76821, France

[6]Genetic department, Regional Hospital, 14 Avenue de l¿Hôpital, Orléans, 45100, France

关键词: Anxiety;    Cognition;    Sociability;    BKCa channel;    BMS-204352;    Fragile X Syndrome;   

Others  :  1150178
DOI  :  10.1186/s13023-014-0124-6

 received in 2014-02-10, accepted in 2014-07-21,  发布年份 2014

【 摘 要 】

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 ?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.

【 授权许可】

   
2014 Hébert et al.; licensee Biomedcentral Ltd.

【 图 表 】

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