Genetic Deletion of Akt3 Induces an Endophenotype Reminiscent of Psychiatric Manifestations in Mice

Abstract

The protein kinase B (PKB/Akt), found in three distinctive isoforms (PKBα/Akt1, PKBβ/Akt2, PKBγ/Akt3), is implicated in a variety of cellular processes such as cell development, growth and survival. Although Akt3 is the most expressed isoform in the brain, its role in cerebral functions is still unclear. In the present study, we investigated the behavioral, electrophysiological and biochemical consequences of Akt3 deletion in mice. Motor abilities, spatial navigation, recognition memory and LTP are intact in the Akt3 knockout (KO) mice. However, the prepulse inhibition, three-chamber social, forced swim, tail suspension, open field, elevated plus maze and light-dark transition tests revealed an endophenotype reminiscent of psychiatric manifestations such as schizophrenia, anxiety and depression. Biochemical investigations revealed that Akt3 deletion was associated with reduced levels of phosphorylated GSK3α/β at serine 21/9 in several brain regions, although Akt1 and Akt2 levels were unaffected. Notably, chronic administration of lithium, a mood stabilizer, restored the decreased phosphorylated GSK3α/β levels and rescued the depressive and anxiety-like behaviors in the Akt3 KO mice. Collectively, our data suggest that Akt3 might be a critical molecule underlying psychiatric-related behaviors in mice.

Akt3 deletion in mice impairs spatial cognition and hippocampal CA1 long long‐term potentiation through downregulation of mTOR

“…Rapamycin has no effect on basal synaptic transmission and LTP induction by a single tetanus. 30 Consistent with our results, a recent study 39 reported that NMDAr-dependent LTP in Akt3-KO mice can be induced. Although either LTP or long-LTP could be induced in Akt1-KO mice, the amplitudes of LTP or early and late long-LTP were slightly reduced in comparison with WT mice.…”

Akt3 inhibits adipogenesis and protects from diet-induced obesity via signaling pathway

“…For example, Akt3 is highly expressed in the brain, and its deficiency leads to a number of cognitive and behavioral derangements in mice (48)(49)(50)(51). While we cannot exclude contribution of behavioral changes to increased adiposity in Akt3…”

Analysis of Gene Expression Variance in Schizophrenia Using Structural Equation Modeling

“…Such a central position in an interrelated network of intracellular signaling implies a role in many cellular and organismal processes, including development. Multiple functional and genetic studies (Howell et al, 2017) clearly indicate the important role of this gene in brain development and suggest involvement in SCZ, and deletion of the gene in mice results in a phenotype reminiscent of a psychiatric manifestation (Bergeron et al, 2017). In addition, the RP11–370K11.1 gene, one of the differentially-expressed genes identified in the same dataset (Evgrafov et al, 2017), is located within AKT3 gene, and one of the SNPs strongly associated with SCZ resides within RP11–370K11.1 .…”