Convergent evidence for impaired AKT1-GSK3β signaling in schizophrenia

ES Emamian, D Hall, MJ Birnbaum, M Karayiorgou… - Nature …, 2004 - nature.com
Nature genetics, 2004nature.com
AKT-GSK3β signaling is a target of lithium and as such has been implicated in the
pathogenesis of mood disorders. Here, we provide evidence that this signaling pathway also
has a role in schizophrenia. Specifically, we present convergent evidence for a decrease in
AKT1 protein levels and levels of phosphorylation of GSK3β at Ser9 in the peripheral
lymphocytes and brains of individuals with schizophrenia; a significant association between
schizophrenia and an AKT1 haplotype associated with lower AKT1 protein levels; and a …
Abstract
AKT-GSK3β signaling is a target of lithium and as such has been implicated in the pathogenesis of mood disorders. Here, we provide evidence that this signaling pathway also has a role in schizophrenia. Specifically, we present convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK3β at Ser9 in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype associated with lower AKT1 protein levels; and a greater sensitivity to the sensorimotor gating–disruptive effect of amphetamine, conferred by AKT1 deficiency. Our findings support the proposal that alterations in AKT1-GSK3β signaling contribute to schizophrenia pathogenesis and identify AKT1 as a potential schizophrenia susceptibility gene. Consistent with this proposal, we also show that haloperidol induces a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for an impaired function of this signaling pathway in schizophrenia.
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