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.
Highlights
Schizophrenia is a common neuropsychiatric disorder, characterized by positive and negative symptomatology and cognitive disability
Our results identify a novel and non-redundant role for Akt3 in prefrontal cortical and hippocampal-mediated cognitive function, identify potential neurobiological mechanisms underlying association of the AKT3 gene with schizophrenia relevant to cortical development, and identify Akt3 as a critical determinant of AKT signaling in the brain
Akt3 mice with one (Akt3-/+) or zero (Akt3-/-) alleles did not differ from WT (Akt3+/+) mice in a comprehensive general health screen (S1 Table), demonstrating physical capability for performing the subsequent battery of behavioral tasks
Summary
Schizophrenia is a common neuropsychiatric disorder, characterized by positive (i.e. hallucinations, delusions) and negative symptomatology (i.e. flat affect, social withdrawal, lack of motivation) and cognitive disability. Large-scale genetic studies of schizophrenia have identified several genomic loci and gene pathways that increase risk. Overlap of risk loci and antipsychotic drug gene targets has recently been reported [7], suggesting a link between disease etiology and antipsychotic mechanisms of action. Given the increasing understanding of the genetic basis of schizophrenia, a critical step in mental illness research is identification of mechanisms and characterization of the in vivo function of risk genes. Such validation is necessary to identify novel therapeutic targets of pathophysiological relevance
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