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Modeling the Role of Impaired Akt Kinase Signaling in the Susceptibility to Stress
Author(s) -
Willock Christine D,
Berdux Nicholas C,
Franke Thomas F
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1119.20
Subject(s) - protein kinase b , akt1 , pi3k/akt/mtor pathway , social defeat , neuroscience , antidepressant , conditional gene knockout , psychology , endocrinology , medicine , signal transduction , biology , hippocampus , phenotype , genetics , gene
Background Akt kinase plays a key role in neuronal cell function and survival. Biochemical studies on human postmortem brains indicate significant changes in Akt signaling in depression and suicide. AKT1 mutations also are a liability in psychiatric diseases such as schizophrenia. These noteworthy findings suggest an important role for intact Akt signaling in mood regulation. Methods Our studies have examined mouse models of Akt deficiency in anxiety‐and depression‐like behaviors, and their responsiveness to antidepressants and psychostimulants. In addition to genomic Akt knockout mice for all three Akt isoforms ( Akt1 , Akt2 and Akt3 ), we employed Cre ‐dependent recombination to produce Akt1 deficiency in specific brain regions and neuron populations. Results Following the social defeat regimen, Akt1 –deficient mice exhibited increased susceptibility to the detrimental effects of chronic stress. Antidepressant treatment failed to ameliorate depression‐like behaviors in the mutants when compared to wild‐type controls. Mice with conditional Akt1 deficiency exhibited a spectrum of phenotypes after completing the chronic social defeat paradigm: Akt1 ablation in the frontal cortex significantly decreased resilience, while ablation in other brain areas and specific neuron populations increased resilience. Similarly, ablation of Akt1 in different brain regions produced distinct and opposing results when measuring locomotor responsiveness to cocaine. Discussion Our results in Akt1 ‐mutant mice converge with biochemical and genetic findings in neuropsychiatric patients and confirm the critical requirement for intact Akt signaling in mood regulation. Based on our findings in conditional Akt1 mutant mice, we predict a significant role for frontal cortical Akt signaling in stress resilience and antidepressant response. Our experiments suggest conditional Akt1 mutant mice as a tractable genetic model to investigate brain region‐specific contributions of Akt signaling to mood regulation. These mutants aid in understanding how circuit‐specific Akt1 deficiencies may become liabilities Conditional Akt1 ‐mutant mice also illustrate specific contributions of Akt signaling to the function and output of distinct neuronal circuits. Support or Funding Information This work was supported in part by NIH grants DA032280, OD018339 and OD018340, and by American Foundation for Suicide Prevention (AFSP) award SRG‐1‐135‐11.