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Mol Psychiatry. 2016 Oct 18. doi: 10.1038/mp.2016.163. [Epub ahead of print]

Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models.

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Child Study Center, Yale University, New Haven, CT, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Hussman Institute for Autism, Baltimore, MD, USA.
Department of Psychiatry, Yale University, New Haven, CT, USA.
Department of Developmental and Stem Cell Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Chemistry, Yale University, New Haven, CT, USA.
Dorris Neuroscience Center, Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, USA.
Plymouth University School of Medicine, Plymouth UK.
UC Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Department of Neurobiology, Yale University, New Haven, CT, USA.
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Contributed equally


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.Molecular Psychiatry advance online publication, 18 October 2016; doi:10.1038/mp.2016.163.

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