Isoform-specific roles for AKT in affective behavior, spatial memory, and extinction related to psychiatric disorders

• Main Authors: Helen Wong, Josien Levenga, Lauren LaPlante, Bailey Keller, Andrew Cooper-Sansone, Curtis Borski, Ryan Milstead, Marissa Ehringer, Charles Hoeffer
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2020-12-01
• Series: eLife
• Subjects: extinction; hippocampus; prefrontal cortex; isoform; associative memory; spatial learning
• Online Access: https://elifesciences.org/articles/56630

AKT is implicated in neurological disorders. AKT has three isoforms, AKT1/AKT2/AKT3, with brain cell type-specific expression that may differentially influence behavior. Therefore, we examined single Akt isoform, conditional brain-specific Akt1, and double Akt1/3 mutant mice in behaviors relevant to neuropsychiatric disorders. Because sex is a determinant of these disorders but poorly understood, sex was an experimental variable in our design. Our studies revealed AKT isoform- and sex-specific effects on anxiety, spatial and contextual memory, and fear extinction. In Akt1 mutant males, viral-mediated AKT1 restoration in the prefrontal cortex rescued extinction phenotypes. We identified a novel role for AKT2 and overlapping roles for AKT1 and AKT3 in long-term memory. Finally, we found that sex-specific behavior effects were not mediated by AKT expression or activation differences between sexes. These results highlight sex as a biological variable and isoform- or cell type-specific AKT signaling as potential targets for improving treatment of neuropsychiatric disorders.