Preliminary evidence has raised the possibility that lithium may be therapeutically beneficial for Fragile X. This project will test if the therapeutic target of lithium is inhibition of the enzyme GSK3 by testing if newly developed, highly specific inhibitors of GSK3 reduce behavioral abnormalities in Fragile X mice. Such a finding would support further development of many new GSK3 inhibitors that have been developed by pharmaceutical companies and justify their testing for a Fragile X indication.
9/2013 – Dr. Richard Jope demonstrated the potential of GSK3 inhibitors, including the available drug lithium, to reverse cognitive deficits in Fragile X in mice
Dr. Jope’s lab previously showed that lithium and other more specific inhibitors of the enzyme Glycogen Synthase Kinase 3 can rescue key symptoms in mice bred to mimic Fragile X syndrome, suggesting that these drugs are potentially disease-modifying. These publications take that work a step further by showing that both lithium (at usual therapeutic doses) and investigational GSK3 inhibitors can reverse a number of cognitive deficits in the knockout mice.
The Jope group showed that Fragile X mice are abnormal in novel object recognition, spatial memory, and temporal order memory, and that these GSK3-inhibiting compounds could all reverse these defects, along with associated electrophysiological abnormalities. In the short term, these abnormalities were relatively insensitive to treatment with an mGluR5 antagonist (although other studies suggest that prolonged treatment with mGluR5 antagonists can correct these abnormalities indirectly). This implies that GSK3 inhibitors may have a different spectrum of activity from mGluR5 antagonists.
Dr. Jope won the 2013 FRAXA Pioneer Award for this work.