Knockout of STriatal enriched protein tyrosine phosphatase in mice results in increased ERK1/2 phosphorylation

Authors

  • Deepa V. Venkitaramani,

    1. Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520
    Search for more papers by this author
    • Deepa V. Venkitaramani and Surojit Paul contributed equally to this work.

  • Surojit Paul,

    1. Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520
    Current affiliation:
    1. Department of Neurology, University of New Mexico, Albuquerque, NM 87131
    Search for more papers by this author
    • Deepa V. Venkitaramani and Surojit Paul contributed equally to this work.

  • Yongfang Zhang,

    1. Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520
    Search for more papers by this author
  • Pradeep Kurup,

    1. Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520
    Search for more papers by this author
  • Li Ding,

    1. Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520
    Search for more papers by this author
  • Lyal Tressler,

    1. Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520
    Search for more papers by this author
  • Melanie Allen,

    1. Pfizer Global Research and Development, Groton, Connecticut 06340
    Search for more papers by this author
  • Rosalba Sacca,

    1. Pfizer Global Research and Development, Groton, Connecticut 06340
    Search for more papers by this author
  • Marina R. Picciotto,

    1. Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, Connecticut 06508
    2. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508
    Search for more papers by this author
  • Paul J. Lombroso

    Corresponding author
    1. Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520
    2. Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, Connecticut 06508
    3. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508
    • Child Study Center, SHM I-270, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
    Search for more papers by this author

Abstract

STriatal Enriched protein tyrosine Phosphatase (STEP) is a brain-specific protein that is thought to play a role in synaptic plasticity. This hypothesis is based on previous findings demonstrating a role for STEP in the regulation of the extracellular signal-regulated kinase1/2 (ERK1/2). We have now generated a STEP knockout mouse and investigated the effect of knocking out STEP in the regulation of ERK1/2 activity. Here, we show that the STEP knockout mice are viable and fertile and have no detectable cytoarchitectural abnormalities in the brain. The homozygous knockout mice lack the expression of all STEP isoforms, whereas the heterozygous mice have reduced STEP protein levels when compared with the wild-type mice. The STEP knockout mice show enhanced phosphorylation of ERK1/2 in the striatum, CA2 region of the hippocampus, as well as central and lateral nuclei of the amygdala. In addition, the cultured neurons from KO mice showed significantly higher levels of pERK1/2 following synaptic stimulation when compared with wild-type controls. These data demonstrate more conclusively the role of STEP in the regulation of ERK1/2 activity. Synapse 63:69–81, 2009. © 2008 Wiley-Liss, Inc.

Ancillary