eLife (Dec 2020)

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

  • Helen Wong,
  • Josien Levenga,
  • Lauren LaPlante,
  • Bailey Keller,
  • Andrew Cooper-Sansone,
  • Curtis Borski,
  • Ryan Milstead,
  • Marissa Ehringer,
  • Charles Hoeffer

DOI
https://doi.org/10.7554/eLife.56630
Journal volume & issue
Vol. 9

Abstract

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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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