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, Neal J Ferrick, Allison M Terlizzi, Nicole Yohn, Eric Koenigsberg, David A Liebelt, R Suzanne Zukin, Newton H Woo, Michael R Tranfaglia, Natalia Louneva, Steven E Arnold, Steven J Siegel, Francois V Bolduc, Thomas V McDonald, Thomas A Jongens, Sean M J McBride

Index: J. Neurosci. 35(1) , 396-408, (2015)

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Abstract

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. Copyright © 2015 the authors 0270-6474/15/350396-13$15.00/0.