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

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.

• Authors: 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
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 35 Issue 1 Pg. 396-408 (Jan 07 2015) ISSN: 1529-2401 [Electronic] United States
• PMID: 25568131 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015 the authors 0270-6474/15/350396-13$15.00/0.

Chemical References

• Phosphodiesterase 4 Inhibitors
• Cyclic Nucleotide Phosphodiesterases, Type 4

Topics

• Animals
• Animals, Genetically Modified
• Cyclic Nucleotide Phosphodiesterases, Type 4 (genetics, metabolism)
• Disease Models, Animal
• Drosophila
• Female
• Fragile X Syndrome (drug therapy, enzymology, genetics)
• Male
• Mice
• Mice, Knockout
• Neuronal Plasticity (drug effects, physiology)
• Phosphodiesterase 4 Inhibitors (pharmacology, therapeutic use)