Abstract
Recent advances in understanding the pathophysiological mechanisms contributing to fragile X syndrome (FXS) have increased optimism that drug interventions can provide significant therapeutic benefits. Based on evidence that glycogen synthase kinase-3 (GSK3) is abnormally active in brain regions in the Fmr1 knockout mouse, there is substantial evidence that inhibitors of GSK3 reverse many abnormalities in Fmr1 knockout mice. GSK3 inhibitors that have been tested include lithium, a drug approved for use in human patients, as well as several more selective inhibitors of GSK3. Lithium was first found to improve behaviors in the Drosophila model of FXS. In Fmr1 knockout mice, administration of lithium or other GSK3 inhibitors significantly improved heightened audiogenic seizure susceptibility, hyperactive locomotor behavior, passive avoidance learning, sociability behaviors, macroorchidism, neuronal spine morphology, protein synthesis, astrogliosis, neural plasticity measured electrophysiologically as long-term depression or long-term potentiation, adult hippocampal neurogenesis, novel object recognition, temporal ordering cognition, and spatial processing. A pilot clinical trial of lithium in patients with FXS also found improvements in several behaviors. Taken together, these findings indicate that lithium and other inhibitors of GSK3 are promising candidate therapeutic agents for treating FXS.
