subunits, and thereby reduced global protein synthesis (Kimball, 1999; Quevedo et al., 2000).
Therefore, elevated GSK3 activity would be expected to generally diminish global protein
translation, though translation of some mRNAs are increased upon phosphorylation of the eIF2B
target eIF2α (Kimball, 1999). Elevated GSK3 activity in FX mouse brains could be an attempt to
compensate for FMRP loss and the associated increase in translation of mRNAs usually bound
by it. If so, a reactive increase in GSK3 activity may produce a significant component of the FXS
pathology. However, given the finding that protein synthesis inhibitors reduce the proclivity for
prolonged, epileptogenic discharges in FX hippocampal slices (Chuang et al., 2005), it might
also be expected that GSK3 activity inhibitors would generally elevate and thereby possibly
exacerbate FX seizure incidence, and the imbalance in protein translation created in the absence
of FMRP. In this light, the clinical benefits of GSK3 inhibition might stem more from more
direct effects on proteins misexpressed in the absence of FMRP such as MAP1B. MAP1B, a
substrate for GSK3, may have direct relevance to the changes in neuronal spine morphology
observed in FXS. The results presented here predict that mode I phosphorylation of MAP1B
would be elevated in the FX mouse brain. Therefore, the benefit of reduced phosphorylation of
MAP1B or similar targets in the FX brain might outweigh any global elevation in protein
synthesis caused by GSK3 inhibitors in FX mice.
(****) Supplemental Text 4
Also potentially consistent with the relevance of glycogen regulation to the results
presented here, chemically induced seizures in mouse strains have a decreased onset with
increased brain glycogen content (Bernard-Helary et al., 2000). Any elevations of brain glycogen