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Nat Genet. 2004 Feb;36(2):131-7. Epub 2004 Jan 25.

Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia.

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The Rockefeller University, Laboratory of Human Neurogenetics, 1230 York Avenue, Box #313, New York, New York 10021, USA.


AKT-GSK3beta 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 GSK3beta 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-GSK3beta 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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