Akt signaling in fear memory processing and depression‐like behaviors

Background The Akt/PKB family of serine/threonine kinases plays a key role in neuronal cell function. Mutations in human AKT genes are found in human schizophrenic subjects, and other neurodevelopmental and psychiatric disorders. Genes encoding the three Akt isoforms ( Akt1, Akt2, Akt3 ) are expressed in the mouse brain suggesting that Akt ‐mutant mice are suitable models to understand the consequences of AKT gene dysfunction in the human brain. Methods To model the impact of Akt genotypes on fear memory processing and depression‐like behaviors, we used knockout strains for mouse Akt1 , Akt2 and Akt3 to examine behavioral and biochemical phenotypes. Results Mice deficient for Akt genes had specific behavioral phenotypes during the acquisition and processing of fear memories. To complement our results with a pharmacological approach, we also inhibited Akt with an allosteric inhibitor. Baseline anxiety levels in naive Akt ‐mutant mice or wild‐type littermates with inhibited Akt signaling were not altered. Acute stress exposure of Akt ‐mutant or inhibitor‐treated mice resulted in depression‐like behavioral responsiveness. Akt knockout mice exhibited an increased susceptibility to chronic stress and decreased responsiveness to antidepressant treatment. Discussion Our data in Akt ‐mutant mice converge with genetic findings in human subjects to support a critical role for Akt signaling in cognition and mood regulation. Our findings define the physiological contribution of selected Akt kinase isoforms to fear memory processing and the resilience to chronic stress. Our results support the study of Akt isoforms as diagnostic markers and therapeutic targets for treatment of neurodevelopmental and psychiatric disorders. This work is supported in part by NIH grants DA032280 and OD018339, and AFSP.