Contribution of hyperactive glycogen synthase kinase-3 (gsk3) to impaired neurogenesis and cognition in mice

The overall goals of this research were to examine the regulatory actions of glycogen synthase kinase-3 (GSK3) in adult mouse hippocampal neurogenesis and in mouse cognitive functions in order to gain further insight regarding the function of GSK3 in the healthy and diseased central nervous system. Focusing on differences between male and female mice, we found that hippocampal neurogenesis was impaired by hyperactive GSK3 in both sexes, but was improved by environmental enrichment in male, but not female, mice. Chronic stress reduced neurogenesis in male mice, but not in female mice. Environmental enrichment and chronic stress inhibited, and activated, respectively, GSK3 in male hippocampus but did not alter GSK3 in female hippocampus. Thus, environmental factors and GSK3 both regulate hippocampal neurogenesis, but do so differently in male and female mice. The accumulating reports that inhibition of GSK3 using lithium or other specific GSK3 inhibitors ameliorates cognitive impairments in multiple disorders were reviewed, which was likely due to reducing several detrimental actions of GSK3 that impair cognition. We tested if GSK3 inhibitors ameliorate cognitive deficits in the mouse model of Fragile X syndrome (FXS), with deletion of the fragile X mental retardation 1 (Fmr1) gene. Chronic lithium treatment during adolescence or adulthood ameliorated several cognitive impairments in Fmr1 knockout mice. Withdrawal of lithium for four weeks reinstated the learning deficits in Fmr1 knockout mice. To determine if the effect of lithium on cognition was due to its inhibition of GSK3, Fmr1 knockout mice were treated with two specific GSK3 inhibitors. We found that inhibition of GSK3, but not of metabotropic glutamate receptor-5, rescued learning in novel object detection, temporal ordering for objects, and coordinate and categorical spatial processing tasks. Thus, abnormally active GSK3 contributes to cognitive dysfunction in FXS, supporting GSK3 as a potential therapeutic target. Overall, this project provides novel insights into the function of GSK3 in two neurologic processes and supports GSK3 as an important regulator of adult neurogenesis and of cognitive processes in FXS.