Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia

Nat Genet. 2004 Feb;36(2):131-7. doi: 10.1038/ng1296. Epub 2004 Jan 25.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antipsychotic Agents / pharmacology
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Haloperidol / pharmacology
  • Haplotypes
  • Humans
  • Phosphorylation / drug effects
  • Phosphotransferases / drug effects
  • Phosphotransferases / metabolism
  • Protein-Serine-Threonine Kinases / drug effects
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins*
  • Schizophrenia / enzymology*
  • Schizophrenia / genetics
  • Schizophrenia / metabolism
  • Serine / metabolism
  • Signal Transduction / physiology*

Substances

  • Antipsychotic Agents
  • Proto-Oncogene Proteins
  • Serine
  • Phosphotransferases
  • AKT1 protein, human
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Haloperidol