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.
Highlights
Present both pre- and post-synaptically, FMRP associates with and suppresses the translation of mRNA important for synaptic function[4,5]
Multiple drug classes have shown evidence of therapeutic efficacy in fragile X animal models; many have been validated via acute dosing in limited model systems
The pro-cognitive effects of PDE4 inhibitors are potentially beneficial to humans with mosaic fragile X, a common presentation in males with the fragile X mutation and a universal condition in females with fragile X
Summary
Present both pre- and post-synaptically, FMRP associates with and suppresses the translation of mRNA important for synaptic function[4,5]. The learning deficit was rescued by crossing the Dmfr[13] allele onto a genetic background lacking the fly dunce gene (Dnc), the single Drosophila PDE4 gene These findings were extended by Choi and coworkers to a Drosophila model in which Dmfr[1] was completely absent[8]. FXS patients display a range of neuropsychiatric symptoms including intellectual disability, delayed language acquisition, poor social interaction, hyperarousal, hypersensitivity, repetitive behaviors, disrupted sleep, attention deficit hyperactivity disorder and autism[2] These behavioral changes are modeled in adult male fmr[1] KO mice which display a spectrum of behavioral phenotypes due to the fmr[1] gene deletion[6]. In both FXS patients and the fmr[1] KO mice, there are alterations in the density, size, shape and maturity of dendritic spines, the principle recipients of excitatory inputs from other neurons[30,31]
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