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PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome
Journal article   Open access   Peer reviewed

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome

Catherine H Choi, Brian P Schoenfeld, Eliana D Weisz, Aaron J Bell, Daniel B Chambers, Joseph Hinchey, Richard J Choi, Paul Hinchey, Maria Kollaros, Michael J Gertner, …
The Journal of neuroscience, v 35(1), pp 396-408
07 Jan 2015
DOI: https://doi.org/10.1523/JNEUROSCI.1356-12.2015
PMID: 25568131
url
https://doi.org/10.1523/JNEUROSCI.1356-12.2015View
Published, Version of Record (VoR)CC BY-NC-SA V4.0,  Open

Abstract

Animals Animals, Genetically Modified Cyclic Nucleotide Phosphodiesterases, Type 4 - genetics Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism Disease Models, Animal Drosophila Female Fragile X Syndrome - drug therapy Fragile X Syndrome - enzymology Fragile X Syndrome - genetics Male Mice Mice, Knockout Neuronal Plasticity - drug effects Neuronal Plasticity - physiology Phosphodiesterase 4 Inhibitors - pharmacology Phosphodiesterase 4 Inhibitors - therapeutic use
Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.

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