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Multiple Behavior Phenotypes of the Fragile-X Syndrome Mouse Model Respond to Chronic Inhibition of
Mark E Gurney1, Patricia Cogram2,3,4, Robert M Deacon2,3,4
1Tetra Discovery Partners, Inc, Grand Rapids, MI, USA. mark@tetradiscovery.com.
Abstract:
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.
Insights
BPN14770, a novel drug, improved behaviors and brain structure in a mouse model of Fragile X syndrome (FXS). These benefits persisted after treatment cessation, suggesting therapeutic potential for FXS and related disorders.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Fragile X syndrome (FXS) is characterized by intellectual disability and autism spectrum disorder, linked to silencing of the FMR1 gene.
- Dysregulation of cyclic adenosine monophosphate (cAMP) metabolism is a hallmark of FXS in patients and animal models.
Purpose of the Study:
- To investigate the therapeutic potential of BPN14770, a phosphodiesterase-4D negative allosteric modulator (PDE4D-NAM), in a mouse model of FXS.
Main Methods:
- Adult male FMR1 knockout mice and control C57BL6 mice were treated daily with BPN14770 for 14 days.
- Behavioral assessments included hyperarousal, social interaction, nesting, and marble burying.
- Dendritic spine morphology was analyzed.
Main Results:
- BPN14770 treatment reduced hyperarousal and improved social interaction and natural behaviors in FXS mice.
- Improvements in dendritic spine morphology were observed.
- No adverse behavioral effects were noted in control mice.
- Therapeutic benefits persisted for two weeks after drug washout.
Conclusions:
- BPN14770 demonstrates significant therapeutic potential for Fragile X syndrome.
- The drug may also be beneficial for other disorders associated with decreased cAMP signaling.
