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

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.