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

Authors

  • Tatiana V. Lipina,

    Corresponding author
    1. Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada
    • Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave. Room 860, Toronto, Ontario M5G 1X5
    Search for more papers by this author
    • Tatiana V. Lipina and Oksana Kaidanovich-Beilin contributed equally to this work.

  • Oksana Kaidanovich-Beilin,

    1. Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada
    Search for more papers by this author
    • Tatiana V. Lipina and Oksana Kaidanovich-Beilin contributed equally to this work.

  • Satish Patel,

    1. Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada
    Search for more papers by this author
  • Min Wang,

    1. Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8, Canada
    Search for more papers by this author
  • Steven J. Clapcote,

    1. Faculty of Biological Sciences, Institute of Membrane and Systems Biology, 6.31e Garstang Building, University of Leeds, Leeds LS2 9JT, United Kingdom
    Search for more papers by this author
  • Fang Liu,

    1. Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8, Canada
    Search for more papers by this author
  • James R. Woodgett,

    1. Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada
    2. University of Toronto, Departments of Medical Biophysics and Molecular and Medical Genetics, Toronto, Ontario, M5S 1A1, Canada
    Search for more papers by this author
  • John C. Roder

    1. Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada
    2. University of Toronto, Departments of Medical Biophysics and Molecular and Medical Genetics, Toronto, Ontario, M5S 1A1, Canada
    Search for more papers by this author

Abstract

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. Synapse, 2010. © 2010 Wiley-Liss, Inc.

Ancillary