|Glycogen synthase kinase-3 and Fragile X
by Richard Jope and Chris Yuskaitis, 5/30/2008
Fragile X syndrome is modeled in mice by knocking out expression of the protein encoded by the FMR1 gene. Studies in these mice and other model systems have allowed investigators to identify potential leads for developing therapeutic interventions in Fragile X syndrome. One of these therapeutic candidates is lithium, a drug already approved for use in human patients for the treatment of other conditions. Another therapeutic lead is to use drugs, such as MPEP, that block the activity of metabotropic glutamate receptors because these receptors are over-active in Fragile X syndrome.
Based on these leads for treatments of Fragile X syndrome that were developed in other laboratories, we are investigating the potential mechanisms that may be involved in these therapeutic interventions. Recent research has identified an important enzyme, called glycogen synthase kinase-3 (GSK3), as the target of lithium in other diseases. Lithium directly inhibits GSK3 to reduce its activity, which results in several modifications in neuronal functions. Therefore, we will examine if GSK3 also might be the target of lithium in Fragile X syndrome. These experiments will test the ability of different treatment regimens with lithium to inhibit GSK3 in brain regions of FMRP knockout mice. This investigation will provide the first information about GSK3 with relation to Fragile X syndrome to examine further the possibility that agents that inhibit GSK3 may provide therapeutic benefits. To do so, this laboratory is following several steps to test if GSK3 is an important pharmacological target in Fragile X syndrome. These include examining GSK3 in brain regions of FMRP knockout mice to test how effective lithium is in inhibiting GSK3 in this condition and testing if there is a therapeutic interaction between treatments with lithium and MPEP. Altogether, this project will follow these promising new leads to test if GSK3 is likely to be a valid therapeutic target in Fragile X syndrome.
The findings of this study may be particularly important for two reasons. First, GSK3 regulates many critical functions in the brain, so inhibition of this important enzyme could have multiple consequences that may improve neuronal functions associated with Fragile X syndrome. Second, lithium is already safely used in human adolescents and adults for effectively inhibiting GSK3, so if GSK3 is proven to be an important factor in Fragile X syndrome there is already a drug available for use.