Glycogen synthase kinase-3: a promising therapeutic target for fragile x syndrome.

Marjelo A Mines,Richard S Jope

doi:10.3389/fnmol.2011.00035

Abstract

Recent advances in understanding the pathophysiological mechanisms contributing to fragile X syndrome (FXS) have increased optimism that drug interventions can provide significant therapeutic benefits. FXS results from inadequate expression of functional fragile X mental retardation protein (FMRP). FMRP may have several functions, but it is most well-established as an RNA binding protein that regulates translation, and it is thought that by this mechanism FMRP is capable of affecting numerous cellular processes by selectively regulating protein levels. The multiple cellular functions regulated by FMRP suggest that multiple interventions may be required for reversing the effects of deficient FMRP. Evidence that inhibitors of glycogen synthase kinase-3 (GSK3) may contribute to the therapeutic treatment of FXS is reviewed here. Lithium, a GSK3 inhibitor, improved function in the Drosophila model of FXS. In mice lacking FMRP expression (FX mice), GSK3 is hyperactive in several brain regions. Significant improvements in several FX-related phenotypes have been obtained in FX mice following the administration of lithium, and in some case other GSK3 inhibitors. These responses include normalization of heightened audiogenic seizure susceptibility and of hyperactive locomotor behavior, enhancement of passive avoidance learning retention and of sociability behaviors, and corrections of macroorchidism, neuronal spine density, and neural plasticity measured electrophysiologically as long term depression. A pilot clinical trial of lithium in patients with FXS also found improvements in several measures of behavior. Taken together, these findings indicate that lithium and other inhibitors of GSK3 are promising candidate therapeutic agents for treating FXS.

Highlights

During the last few years there has been tremendous progress in understanding the pathological mechanisms underlying fragile X syndrome (FXS)
In FX mice, heightened susceptibility to audiogenic seizures is almost certainly controlled by inhibiting glycogen synthase kinase-3 (GSK3), since three structurally dissimilar GSK3 inhibitors normalized this susceptibility without affecting responses of wild-type mice
Evidence suggests that locomotor hyperactivity can be reduced by targeting GSK3 based on the normalizing actions of the GSK3 inhibitor SB216763 as well as lithium

Summary

MOLECULAR NEUROSCIENCE

Glycogen synthase kinase-3: a promising therapeutic target for fragile X syndrome. Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA. Evidence that inhibitors of glycogen synthase kinase-3 (GSK3) may contribute to the therapeutic treatment of FXS is reviewed here. Significant improvements in several FX-related phenotypes have been obtained in FX mice following the administration of lithium, and in some case other GSK3 inhibitors. These responses include normalization of heightened audiogenic seizure susceptibility and of hyperactive locomotor behavior, enhancement of passive avoidance learning retention and of sociability behaviors, and corrections of macroorchidism, neuronal spine density, and neural plasticity measured electrophysiologically as long term depression. A pilot clinical trial of lithium in patients with FXS found improvements in several measures of behavior Taken together, these findings indicate that lithium and other inhibitors of GSK3 are promising candidate therapeutic agents for treating FXS

INTRODUCTION

Mines and Jope