Two new papers from FRAXA-funded researcher Dr. Richard Jope demonstrate the potential of GSK3 inhibitors, including the available drug, lithium, to reverse learning deficits in fragile X.
Dr. Jope has previously shown that lithium and other more specific inhibitors of the enzyme Glycogen Synthase Kinase 3 (GSK3) can rescue key symptoms in Fragile X mice. These new publications take that study a step further by showing that lithium (at usual therapeutic doses) and investigational GSK3 inhibitors could reverse a number of cognitive deficits in the 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. Furthermore, 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, and may make an excellent combination treatment with mGluR5 antagonists.