Multiple behavior phenotypes of the fragile-X syndrome mouse model respond to chronic inhibition of phosphodiesterase-4D (PDE4D)
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Fragile-X syndrome (FXS) patients display intellectual disability and autism spectrum disorder due to silencing of the X-linked, fragile-X mental retardation-1 (FMR1) gene. Dysregulation of cAMP metabolism is a consistent finding in patients and in the mouse and fly FXS models. We therefore explored if BPN14770, a prototypic phosphodiesterase-4D negative allosteric modulator (PDE4D-NAM) in early human clinical trials, might provide therapeutic benefit in the mouse FXS model. Daily treatment of adult male fmr1 C57Bl6 knock-out mice with BPN14770 for 14 days reduced hyperarousal, improved social interaction, and improved natural behaviors such as nesting and marble burying as well as dendritic spine morphology. There was no decrement in behavioral scores in control C57Bl6 treated with BPN14770. The behavioral benefit of BPN14770 persisted two weeks after washout of the drug. Thus, BPN14770 may be useful for the treatment of fragile-X syndrome and other disorders with decreased cAMP signaling.
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Animal studies have shown that a phosphordiasterase 4DE inhibitor can rescue features of FXS in the KO mouse model and Drosophila model and can raise cAMP levels to normal.
“Recent animal studies have shown that an inhibitor of cAMP breakdown called a phosphordiasterase 4DE inhibitor can rescue features of FXS in the KO mouse model and Drosophila model and can raise the cAMP levels to normal [141, 142].”
From An Update on Psychopharmacological Treatment of Autism Spectrum Disorder (2022) · cites this paper as [142]
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- Authors
- Gurney, M. E., Cogram, P., Deacon, R. M., Rex, C., & Tranfaglia, M.
- Affiliations
- Tetra Therapeutics (United States) (US)
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Afraxis (United States) (US)
- Fraxa Research Foundation (US)
- Corresponding author
- Gurney, Mark E.
- Venue
- Scientific Reports
- Published
- 2017-11-07
- Volume
- 7
- Issue
- 1
- Pages
- 14653-14653
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5677090
- OpenAlex
- W2766431378
- Cited by
- 69
- References
- 58
- Citations by year
- 2025: 10 · 2024: 10 · 2023: 6 · 2022: 8 · 2021: 16 · 2020: 8 · 2019: 7 · 2018: 4
- FWCI
- 3.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Universidad de Chile (submittedVersion, cc-by-nc-nd)
- Funders
- FRAXA Research Foundation
- National Institute of Neurological Disorders and Stroke (U01NS078034, NS078034)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- fragile X syndrome, PDE4D, negative allosteric modulators, cAMP signaling, Fmr1 knockout mice, intellectual disability, autism spectrum disorder, hyperarousal, social interaction, nesting behavior, marble burying, dendritic spine morphology, drug washout
- MeSH terms
- Animals, Behavior, Animal, Disease Models, Animal, Fragile X Syndrome, Male, Mice, Inbred C57BL, Phenotype, Mice, Knockout, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1, Cyclic Nucleotide Phosphodiesterases, Type 4, Phosphodiesterase 4 Inhibitors
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