Genetic and pharmacological evidence for schizophrenia-related Disc1 interaction with GSK-3

Synapse. 2011 Mar;65(3):234-48. doi: 10.1002/syn.20839.


Recent studies have identified disrupted-in-schizophrenia-1 (DISC1) as a strong genetic risk factor associated with schizophrenia. Previously, we have reported that a mutation in the second exon of the DISC1 gene [leucine to proline at amino acid position 100, L100P] leads to the development of schizophrenia-related behaviors in mice. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase that interacts with the N-terminal region of DISC1 (aa 1-220) and has been implicated as an important downstream component in the etiology of schizophrenia. Here, for the first time, we show that pharmacological and genetic inactivation of GSK-3 reverse prepulse inhibition and latent inhibition deficits as well as normalizing the hyperactivity of Disc1-L100P mutants. In parallel to these observations, interaction between DISC1 and GSK-3α and β is reduced in Disc1-L100P mutants. Our data provide genetic, biochemical, and behavioral evidence for a molecular link between DISC1 and GSK-3 in relation to psychopathology and highlights the value of missense mutations in dissecting the underlying and complex molecular mechanisms of neurological disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Blotting, Western
  • Gene Expression Profiling
  • Gene Expression Regulation / genetics
  • Glycogen Synthase Kinase 3 / genetics*
  • Glycogen Synthase Kinase 3 / metabolism*
  • Immunoprecipitation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutation, Missense
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism*


  • Disc1 protein, mouse
  • Nerve Tissue Proteins
  • Glycogen Synthase Kinase 3