Elevated glycogen synthase kinase-3 activity in Fragile X mice: Key metabolic regulator with evidence for treatment potential

NEUROPHARMACOLOGY

卷:56

Article

Min, Wenzhong William¹  Yuskaitis, Christopher J.²  Yan, Qijiang¹  Sikorski, Christopher¹  Chen, Shengqiang¹  Jope, Richard S.²  Bauchwitz, Robert P.¹ 

[1] Columbia Univ, St Lukes Roosevelt Inst Hlth Sci, New York, NY 10019 USA

[2] Univ Alabama Birmingham, Dept Psychiat & Behav Neurobiol, Birmingham, AL 35294 USA

关键词: GSK3;    Fragile X;    Lithium;    mGluR;    Behavior;    Audiogenic seizures;   

DOI  :  10.1016/j.neuropharm.2008.09.017

来源: Elsevier

【 摘 要 】

Significant advances have been made in understanding the underlying defects of and developing potential treatments for Fragile X syndrome (FXS), the most common heritable mental retardation. It has been shown that neuronal metabotropic glutamate receptor 5 (mGluR5)-mediated signaling is affected in FX animal models, with consequent alterations in activity-dependent protein translation and synaptic spine functionality. We demonstrate here that a central metabolic regulatory enzyme, glycogen synthase kinase-3 (GSK3) is present in a form indicating elevated activity in several regions of the FX mouse brain. Furthermore, we show that selective GSK3 inhibitors, as well as lithium, are able to revert mutant phenotypes of the FX mouse. Lithium, in particular, remained effective with chronic administration, although its effects were reversible even when given from birth. The combination of an mGluR5 antagonist and GSK3 inhibitors was not additive. Instead, it was discovered that mGluR5 signaling and GSK3 activation in the FX mouse are coordinately elevated, with inhibition of mGluR5 leading to inhibition of GSK3. These findings raise the possibility that GSK3 is a fundamental and central component of FXS pathology, with a substantial treatment potential. (c) 2008 Elsevier Ltd. All rights reserved.

【 授权许可】

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