Inhibition of STEP 61 ameliorates deficits in mouse and hiPSC-based schizophrenia models

J. Xu, B. J. Hartley, P. Kurup, A. Phillips, A. Topol, M. Xu, C. Ononenyi, E. Foscue, S. M. Ho, T. D. Baguley, N. Carty, C. S. Barros, Ulrich Mueller, S. Gupta, P. Gochman, J. Rapoport, J. A. Ellman, C. Pittenger, B. Aronow, A. C. NairnM. W. Nestor, P. J. Lombroso, K. J. Brennand

Research output: Contribution to journalArticle

Abstract

The brain-specific tyrosine phosphatase, STEP (STriatal-Enriched protein tyrosine Phosphatase) is an important regulator of synaptic function. STEP normally opposes synaptic strengthening by increasing N-methyl D-aspartate glutamate receptor (NMDAR) internalization through dephosphorylation of GluN2B and inactivation of the kinases extracellular signal-regulated kinase 1/2 and Fyn. Here we show that STEP61 is elevated in the cortex in the Nrg1+/- knockout mouse model of schizophrenia (SZ). Genetic reduction or pharmacological inhibition of STEP prevents the loss of NMDARs from synaptic membranes and reverses behavioral deficits in Nrg1+/- mice. STEP61 protein is also increased in cortical lysates from the central nervous system-specific ErbB2/4 mouse model of SZ, as well as in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons and Ngn2-induced excitatory neurons, from two independent SZ patient cohorts. In these selected SZ models, increased STEP61 protein levels likely reflect reduced ubiquitination and degradation. These convergent findings from mouse and hiPSC SZ models provide evidence for STEP61 dysfunction in SZ.

Original languageEnglish (US)
Pages (from-to)271-281
Number of pages11
JournalMolecular Psychiatry
Volume23
Issue number2
DOIs
StatePublished - Feb 1 2018
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Xu, J., Hartley, B. J., Kurup, P., Phillips, A., Topol, A., Xu, M., Ononenyi, C., Foscue, E., Ho, S. M., Baguley, T. D., Carty, N., Barros, C. S., Mueller, U., Gupta, S., Gochman, P., Rapoport, J., Ellman, J. A., Pittenger, C., Aronow, B., ... Brennand, K. J. (2018). Inhibition of STEP 61 ameliorates deficits in mouse and hiPSC-based schizophrenia models. Molecular Psychiatry, 23(2), 271-281. https://doi.org/10.1038/mp.2016.163