title: Inhibition of STEP61ameliorates deficits in mouse and hiPSC-based schizophrenia models.
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 STEP61is 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. STEP61protein 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 STEP61protein levels likely reflect reduced ubiquitination and degradation. These convergent findings from mouse and hiPSC SZ models provide evidence for STEP61dysfunction in SZ.
authors.affiliation: Child Study Center, Yale University, New Haven, CT, USA.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: B J
authors.initials: BJ
authors.lastname: Hartley
authors.affiliation: Child Study Center, Yale University, New Haven, CT, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kurup
authors.affiliation: Hussman Institute for Autism, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Phillips
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Topol
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: M
authors.initials: M
authors.lastname: Xu
authors.affiliation: Child Study Center, Yale University, New Haven, CT, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ononenyi
authors.affiliation: Child Study Center, Yale University, New Haven, CT, USA.
authors.forename: E
authors.initials: E
authors.lastname: Foscue
authors.affiliation: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Developmental and Stem Cell Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: S-M
authors.initials: SM
authors.lastname: Ho
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT, USA.
authors.forename: T D
authors.initials: TD
authors.lastname: Baguley
authors.affiliation: Child Study Center, Yale University, New Haven, CT, USA.
authors.forename: N
authors.initials: N
authors.lastname: Carty
authors.affiliation: Dorris Neuroscience Center, Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, USA.|Plymouth University School of Medicine, Plymouth UK.
authors.forename: C S
authors.initials: CS
authors.lastname: Barros
authors.affiliation: Dorris Neuroscience Center, Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: U
authors.initials: U
authors.lastname: Müller
authors.affiliation: UC Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors.forename: P
authors.initials: P
authors.lastname: Gochman
authors.affiliation: Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Rapoport
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Ellman
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: C
authors.initials: C
authors.lastname: Pittenger
authors.affiliation: UC Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: B
authors.initials: B
authors.lastname: Aronow
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Nairn
authors.affiliation: Hussman Institute for Autism, Baltimore, MD, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Nestor
authors.affiliation: Child Study Center, Yale University, New Haven, CT, USA.|Department of Psychiatry, Yale University, New Haven, CT, USA.|Department of Neurobiology, Yale University, New Haven, CT, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Lombroso
authors.affiliation: 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.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Brennand
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020890:Neuregulin-1 / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate; D017027:Protein Tyrosine Phosphatases; C000591055:striatal-enriched tyrosine phosphatase 61, mouse