Failure to Inactivate Nuclear GSK3β by Ser389-Phosphorylation Leads to Focal Neuronal Death and Prolonged Fear Response

GSK3β plays an essential role in promoting cell death and is emerging as a potential target for neurological diseases. Understanding the mechanisms that control neuronal GSK3β is critical. A ubiquitous mechanism to repress GSK3β involves Akt-mediated phosphorylation of Ser9. Here we show that phosphorylation of GSK3β on Ser389 mediated by p38 MAPK specifically inactivates nuclear GSK3β in the cortex and hippocampus. Using GSK3β Ser389 to Ala mutant mice, we show that failure to inactivate nuclear GSK3β by Ser389 phosphorylation causes neuronal cell death in subregions of the hippocampus and cortex. Although this focal neuronal death does not impact anxiety/depression-like behavior or hippocampal-dependent spatial learning, it leads to an amplified and prolonged fear response. This phenotype is consistent with some aspects of post-traumatic stress disorder (PTSD). Our studies indicate that inactivation of nuclear GSK3β by Ser389 phosphorylation plays a key role in fear response, revealing new potential therapeutic approaches to target PTSD.