Isoform-specific roles for AKT in affective behavior, spatial memory, and extinction related to psychiatric disorders
- University of Colorado, Boulder, United States
Abstract
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.
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All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1-9.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (NS086933)
- Helen Wong
- Josien Levenga
- Lauren E LaPlante
- Bailey N Keller
- Andrew Cooper-Sansone
- Curtis Borski
- Ryan A Milstead
- Charles A Hoeffer
National Institute of Mental Health (MH016880)
- Helen Wong
- Charles A Hoeffer
Jerome LeJeune Foundation (1805)
- Helen Wong
- Andrew Cooper-Sansone
- Charles A Hoeffer
National Institute on Aging (AG 064465)
- Helen Wong
- Lauren E LaPlante
- Charles A Hoeffer
National Institute on Aging (AG052371)
- Ryan A Milstead
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Wong et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Isoform-specific roles for AKT in affective behavior, spatial memory, and extinction related to psychiatric disorders
eLife 9:e56630.
https://doi.org/10.7554/eLife.56630
