PKBγ/AKT3 loss-of-function causes learning and memory deficits and deregulation of AKT/mTORC2 signaling: Relevance for schizophrenia

Abstract

Psychiatric genetic studies have identified genome-wide significant loci for schizophrenia. The AKT3/1q44 locus is a principal risk region and gene-network analyses identify AKT3 polymorphisms as a constituent of several neurobiological pathways relevant to psychiatric risk; the neurobiological mechanisms remain unknown. AKT3 shows prenatal enrichment during human neocortical development and recurrent copy number variations involving the 1q43-44 locus are associated with cortical malformations and intellectual disability, implicating an essential role in early brain development. Here, we investigated the role of AKT3 as it relates to aspects of learning and memory and behavioral function, relevant to schizophrenia and cognitive disability, utilizing a novel murine model of Akt3 genetic deficiency. Akt3 heterozygous (Akt3-/+) or null mice (Akt3-/-) were assessed in a comprehensive test battery. Brain biochemical studies were conducted to assess the impact of Akt3 deficiency on cortical Akt/mTOR signaling. Akt3-/+ and Akt3-/- mice exhibited selective deficits of temporal order discrimination and spatial memory, tasks critically dependent on intact prefrontal-hippocampal circuitry, but showed normal prepulse inhibition, fear conditioned learning, memory for novel objects and social function. Akt3 loss-of-function, reduced brain size and dramatically impaired cortical Akt Ser473 activation in an allele-dose dependent manner. Such changes were observed in the absence of altered Akt1 or Akt2 protein expression. Concomitant reduction of the mTORC2 complex proteins, Rictor and Sin1 identifies a potential mechanism. Our findings provide novel insight into the neurodevelopmental role of Akt3, identify a non-redundant role for Akt3 in the development of prefrontal cortical-mediated cognitive function and show that Akt3 is potentially the dominant regulator of AKT/mTOR signaling in brain.

Analysis of Gene Expression Variance in Schizophrenia Using Structural Equation Modeling

“…In addition to pathways enriched in differentially expressed genes (Wnt, Notch, Serine biosynthesis; Evgrafov et al, 2017), we found that PI3K-Akt signaling has been identified as important in multiple studies of SCZ (Mao et al, 2009; Panaccione et al, 2013; Singh et al, 2013; Topol et al, 2015; Mulligan and Cheyette, 2016; Howell et al, 2017; Wang et al, 2017). Pathway analysis of GWAS data, performed by The Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium (2015) showed enrichment of several GO terms, associated with neuron structure and histone H3-K4 methylation.…”

“…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 .…”

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…”

Gene expression in patient-derived neural progenitors implicates WNT5A signaling in the etiology of schizophrenia

“…The results fit our expectations, showing modest, but still substantial and statistically significant overlap. Genome-wide significant variants are located within two DEX genes, ESAM and non-coding RP11-370K11.1 (located within intron of AKT3, a proposed candidate gene for SCZ (14)), and IL1RAPL1 contains a SNP that is nearly genome-wide significant (rs5943629, p = 5.748x10 -8 ).…”