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

Abstract

a b s t r a c tSignificant 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.

Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome

“…Finally, we found that the rescuing effect of MPEP and GSK inhibitors is quite similar regardless of electrophysiological, behavioral, or biochemical phenotypes, suggesting that mGluR5 and GSK3 may link to each other. Previous studies found that MPEP inhibits GSK3 activity by increasing the inhibitory phosphorylation of GSK3 (Liu et al, 2005;Min et al, 2009;Yuskaitis et al, 2010), whereas combined inhibition of mGluR5 and GSK3 does not cause synergistic effect (Min et al, 2009). Therefore, it is likely that GSK3 is one of the downstream targets of mGluR5.…”

“…We thus tested whether mGluR5 antagonist MPEP could rescue the deficient L-LTP and network recruitment observed in ACC slices of Fmr1 KO mice. Furthermore, GSK3 functions closely to mGluR5 signaling, and excessive expression of GSK3 in cortex has been reported in Fmr1 KO mice (Berry-Kravis et al, 2008; Min et al, 2009). We also tested whether inhibition of GSK3 could rescue L-LTP and network recruitment.…”

“…These findings indicate that mGluR5 antagonist might be a good candidate for therapeutic application. In addition, GSK3 is a newly found signal protein that is important for synaptic plasticity, closely related to mGluR5 signaling and overexpressed in Fmr1 KO mice (Bradley et al, 2012;Guo et al, 2012;Liu et al, 2005;Min et al, 2009). However, the function of GSK3 in FXS is less investigated.…”

The complex genetics in autism spectrum disorders

“…In support of this mGluR hypothesis of Fragile X Syndrome, analysis of double KO Drosophila of dFmr1 (homolog of the human FMR1 gene) and dmGluRA (the Drosophila mGluR) has suggested that these two genes converge to regulate postsynaptic GluR trafficking, synaptic ultrastructure and plasticity, and motor behavior [57][58][59]. 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a potent negative modulator of mGluR5 [60], consistently rescues many FXSrelated deficits in KO mice [50,55,56,[61][62][63], fly [64][65][66] and zebrafish [67], implying the therapeutic potential of FXS using mGluR5 inhibitors. Indeed, multiple human clinical trials with chemicals targeting mGluR5, or mGluRs-related signaling pathways, or presynaptic release of glutamate, such as gamma-aminobutyric acid (GABA) B receptor agonists, are being conducted, and are showing promising, but as yet inconclusive, results with regard to treating FXS [68][69][70][71].…”

“…FMR1-deficient mice show increased locomotor activity in the open-field test, elevated anxiety levels in the mirror-chamber test, and impaired social interaction with unfamiliar partners in multiple tests [52][53][54][55][56]. Interestingly, the FXS-like behavior phenotypes in FMR1 KO mice were rescued by repressing the function of group 1 metabotropic glutamate receptors (Gp1 mGluRs).…”