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

Bauchwitz, Dr. Robert P. (2007) Elevated glycogen synthase kinase 3 activity in Fragile X mice: key metabolic regulator with evidence for treatment potential. [Preprint]

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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 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 active with chronic dosing, although its effects were transient even when given from birth. The combination of 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.

Item Type:Preprint
Keywords:GSK3, Fragile X Syndrome, mental retardation, lithium, autism
Subjects:Neuroscience > Neuropharmacology
ID Code:5925
Deposited By:Bauchwitz, Dr. Robert
Deposited On:10 Feb 2008 03:27
Last Modified:11 Mar 2011 08:57

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