title: Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice.
abstract: Brain-derived neurotrophic factor (BDNF) and STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61) have opposing functions in the brain, with BDNF supporting and STEP61 opposing synaptic strengthening. BDNF and STEP61 also exhibit an inverse pattern of expression in a number of brain disorders, including schizophrenia (SZ). NMDAR antagonists such as phencyclidine (PCP) elicit SZ-like symptoms in rodent models and unaffected individuals, and exacerbate psychotic episodes in SZ. Here we characterize the regulation of BDNF expression by STEP61, utilizing PCP-treated cortical culture and PCP-treated mice. PCP-treated cortical neurons showed both an increase in STEP61 levels and a decrease in BDNF expression. The reduction in BDNF expression was prevented by STEP61 knockdown or use of the STEP inhibitor, TC-2153. The PCP-induced increase in STEP61 expression was associated with the inhibition of CREB-dependent BDNF transcription. Similarly, both genetic and pharmacologic inhibition of STEP prevented the PCP-induced reduction in BDNF expression in vivo and normalized PCP-induced hyperlocomotion and cognitive deficits. These results suggest a mechanism by which STEP61 regulates BDNF expression, with implications for cognitive functioning in CNS disorders.
authors.affiliation: Child Study Center, Yale University, 230 S Frontage Rd., New Haven, CT, 06520, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Child Study Center, Yale University, 230 S Frontage Rd., New Haven, CT, 06520, USA.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kurup
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT, 06520, USA.
authors.forename: Tyler D
authors.initials: TD
authors.lastname: Baguley
authors.affiliation: Child Study Center, Yale University, 230 S Frontage Rd., New Haven, CT, 06520, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Foscue
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT, 06520, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Ellman
authors.affiliation: Department of Psychiatry, Yale University, 300 George St., New Haven, CT, 06520, USA.
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.affiliation: Child Study Center, Yale University, 230 S Frontage Rd., New Haven, CT, 06520, USA. paul.lombroso@yale.edu.|Department of Psychiatry, Yale University, 300 George St., New Haven, CT, 06520, USA. paul.lombroso@yale.edu.|Department of Neurobiology, Yale University, 333 Cedar St., New Haven, CT, 06520, USA. paul.lombroso@yale.edu.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lombroso
mesh_terms: D000818:Animals; D001582:Benzothiepins / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010622:Phencyclidine / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C559038:8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine; D001582:Benzothiepins; D019208:Brain-Derived Neurotrophic Factor; D016194:Receptors, N-Methyl-D-Aspartate; D050882:CREB-Binding Protein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017027:Protein Tyrosine Phosphatases; C000591055:striatal-enriched tyrosine phosphatase 61, mouse; D010622:Phencyclidine
keywords: BDNF; Phencyclidine; STEP inhibitor; Schizophrenia; Ubiquitination