The AKT1genotype could be a potential schizophrenia susceptibility gene. Emamian,Hall, Birnbaum, Karayiorgou and Gogos (2004) showed that the pathogenesis ofschizophrenia were provided by AKT1 signaling pathway. They used severalvariations of kinases that were implicated in synaptic plasticity that areexpressed in various cell types such as peripheral blood lymphoctes. Theirfirst results showed that individuals with schizophrenia had 68% lower levelsof AKT1 kinases than controls, in contrast with the other protein kinases. Theyfound reduced AKT1 levels in the frontal cortex and lymphocytes inschizophrenia patients. Second, they found 5 SNPs of the AKT1 locus in 268families (a total of 335 schizophrenia patients) that were associated withschizophrenia.
These 5 SNPs markers were also associated with frontostriataldopaminergic system in healthy individuals by Tan et al. (2008). They foundthat genetic variation of AKT1 may be linked to dopamine-associated prefrontalcortical function and structure. They found the strongest association withfrontal lobe function with the A allele of the AKT1 SNP rs1130233. To measurethe cortical structural and functional changes in DA signaling, the subjectshad to perform a task (which is linked to cortical DA function) while undergoingfunctional magnetic resonance imaging scanner (fMRI). They found that carriers ofthe A allele had reduced information processing in the PFC.
On top of that,carriers had also reduced gray-matter volume in the right PFC and the caudatenucleus. Besides the AKT1 gene that hasbeen associated with schizophrenia there are more genes, like thedystrobrevin-binding protein 1 (DTNBP1). Dysbindin is believed to play a rolein synaptic plasticity and signal transduction. Numakawa et al. (2004) showedthat the phosphorylation levels of AKT were suppressed by the downregulation ofdysbindin expression. They examined the neurotrophic effect through AKTsignaling pathway as a function of dysbindin. They showed that overexpressionof dysbindin resulted in activation of AKT.
A PI3 kinase inhibitor, LY294002, inhibitedthe activation of AKT by the overexpression of dysbindin. Their data implicatesthat AKT signaling in schizophrenia patients might be caused by reducedexpression of dysbindin.