Rescue of fragile X syndrome phenotypes in Fmr1KO mice by a BKCa channel opener molecule
Open accessAbstract
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.
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Many classic behavioural phenotypes used as preclinical outcome measures are inconsistently observed in Fmr1-knockout mice.
“many of the other classic behavioural phenotypes used as outcome measures in preclinical studies are inconsistently observed in Fmr1-KO mice (such as open field, rotarod, elevated plus-maze, marble burying, self-grooming and most social paradigms).”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [56]
Rescue of these behavioural phenotypes has been difficult to consolidate and to use as a guide for clinical studies.
“As a result, the rescue of these behavioural phenotypes has been difficult to consolidate and to use as a guide for clinical studies30,49,56,64,65.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [56]
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Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome
Berry-Kravis, E. M., Lindemann, L., Jønch, A. E., Apostol, G., Bear, M. F., Carpenter, R. L., Crawley, J. N., Curie, A., Des Portes, V., Hossain, F., et al. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.221 · Cited by 336 · see citing works
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“…or Fmr1 ko mice, however, the allosteric BK channel activator BMS-204352 was shown to reverse behavioural and cellular FXS symptoms in Fmr1 ko mice (Hebert et al., 2014), highlighting the potential of studying sensory filtering mechanisms in animal models for developing pharmaceutical treatments.”
InfluentialTherapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back
Gross, C., Hoffmann, A., Bassell, G. J., & Berry-Kravis, E. M. (2015) · Neurotherapeutics · doi:10.1007/s13311-015-0355-9 · Cited by 105 · see citing works
- Authors
- Hébert, B., Pietropaolo, S., Même, S., Laudier, B., Laugeray, A., Doisne, N., Quartier, A., Lefeuvre, S., Got, L., Cahard, D., Laumonnier, F., Crusio, W. E., Pichon, J., Menuet, A., Perche, O., & Briault, S.
- Affiliations
- Université d'Orléans (FR)
- Centre National de la Recherche Scientifique (FR)
- Centre hospitalier universitaire d'Orléans (FR)
- Université de Tours (FR)
- Corresponding author
- Briault, Sylvain
- ORCID
- Venue
- Orphanet Journal of Rare Diseases
- Published
- 2014-08-01
- Volume
- 9
- Issue
- 1
- Pages
- 124-124
- ISSN
- 1750-1172 (ISSN-L)
- PMC
- PMC4237919
- OpenAlex
- W2142496715
- Cited by
- 100
- References
- 62
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 8 · 2023: 20 · 2022: 6 · 2021: 11 · 2020: 10 · 2019: 11 · 2018: 10 · 2017: 10 · 2016: 4 · 2015: 5 · 2014: 1
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Orphanet Journal of Rare Diseases (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- FRAXA Research Foundation
- March of Dimes Foundation (12-FY05-1198)
- European Commission (241995)
- Fondation de France
- Centre National de la Recherche Scientifique (12-FY05-1198)
- Université d'Orléans
- Université de Bordeaux (12-FY05-1198)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
- Keywords
- fragile X syndrome, Fmr1 knockout mice, dendritic spines, social recognition, anxiety, spatial memory, intellectual disability, autism spectrum disorder, therapeutic target
- MeSH terms
- Animals, Fragile X Syndrome, Humans, Phenotype, Mice, Knockout, Large-Conductance Calcium-Activated Potassium Channel alpha Subunits, Mice, Fragile X Messenger Ribonucleoprotein 1
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