Choi, C.H., Schoenfeld, B.P., Weisz, E.D., Bell, A.J., Chambers, D.B., Hinchey, J., Choi, R.J., Hinchey, P., Kollaros, M., Gertner, M.J., Ferrick, N.J., Terlizzi, A.M., Yohn, N., Koenigsberg, E., Liebelt, D.A., Zukin, R.S., Woo, N.H., Tranfaglia, M.R., Louneva, N., Arnold, S.E., Siegel, S.J., Bolduc, F.V., McDonald, T.V., Jongens, T.A., McBride, S.M. (2015). PDE-4 Inhibition Rescues Aberrant Synaptic Plasticity in Drosophila and Mouse Models of Fragile X Syndrome.  J. Neurosci. 35(1): 396--408.

FBrf0227263

Research paper

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.

PMC4287155 (PMC) (EuropePMC)