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.
Data availability
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.
Reviewing Editor
- Mary Kay Lobo, University of Maryland, United States
Version history
- Received: March 4, 2020
- Accepted: December 15, 2020
- Accepted Manuscript published: December 16, 2020 (version 1)
- Version of Record published: January 6, 2021 (version 2)
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
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