title: Ketamine up-regulates a cluster of intronic miRNAs within the serotonin receptor 2C gene by inhibiting glycogen synthase kinase-3.
abstract: We examined mechanisms that contribute to the rapid antidepressant effect of ketamine in mice that is dependent on glycogen synthase kinase-3 (GSK3) inhibition.
  
  
  
  We measured serotonergic (5HT)-2C-receptor (5HTR2C) cluster microRNA (miRNA) levels in mouse hippocampus after administering an antidepressant dose of ketamine (10 mg/kg) in wild-type and GSK3 knockin mice, after GSK3 inhibition with L803-mts, and in learned helpless mice.
  
  
  
  Ketamine up-regulated cluster miRNAs 448-3p, 764-5p, 1264-3p, 1298-5p and 1912-3p (2- to 11-fold). This up-regulation was abolished in GSK3 knockin mice that express mutant constitutively active GSK3. The GSK3 specific inhibitor L803-mts was antidepressant in the learned helplessness and novelty suppressed feeding depression-like behaviours and up-regulated the 5HTR2C miRNA cluster in mouse hippocampus. After administration of the learned helplessness paradigm mice were divided into cohorts that were resilient (non-depressed) or were susceptible (depressed) to learned helplessness. The resilient, but not depressed, mice displayed increased hippocampal levels of miRNAs 448-3p and 1264-3p. Administration of an antagonist to miRNA 448-3p diminished the antidepressant effect of ketamine in the learned helplessness paradigm, indicating that up-regulation of miRNA 448-3p provides an antidepressant action.
  
  
  
  These findings identify a new outcome of GSK3 inhibition by ketamine that may contribute to antidepressant effects.
authors.affiliation: a Department of Psychiatry and Behavioural Sciences , Miller School of Medicine, University of Miami , Miami , FL , USA.|b Department of Biochemistry and Molecular Biology , Miller School of Medicine, University of Miami , Miami , FL , USA.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Grieco
authors.affiliation: a Department of Psychiatry and Behavioural Sciences , Miller School of Medicine, University of Miami , Miami , FL , USA.|b Department of Biochemistry and Molecular Biology , Miller School of Medicine, University of Miami , Miami , FL , USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Velmeshev
authors.affiliation: a Department of Psychiatry and Behavioural Sciences , Miller School of Medicine, University of Miami , Miami , FL , USA.|b Department of Biochemistry and Molecular Biology , Miller School of Medicine, University of Miami , Miami , FL , USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Magistri
authors.affiliation: c Department of Human Molecular Genetics and Biochemistry , Sackler School of Medicine, Tel Aviv University , Tel Aviv , Israel.
authors.forename: Hagit
authors.initials: H
authors.lastname: Eldar-Finkelman
authors.affiliation: a Department of Psychiatry and Behavioural Sciences , Miller School of Medicine, University of Miami , Miami , FL , USA.|b Department of Biochemistry and Molecular Biology , Miller School of Medicine, University of Miami , Miami , FL , USA.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Faghihi
authors.affiliation: a Department of Psychiatry and Behavioural Sciences , Miller School of Medicine, University of Miami , Miami , FL , USA.|b Department of Biochemistry and Molecular Biology , Miller School of Medicine, University of Miami , Miami , FL , USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Jope
authors.affiliation: a Department of Psychiatry and Behavioural Sciences , Miller School of Medicine, University of Miami , Miami , FL , USA.|b Department of Biochemistry and Molecular Biology , Miller School of Medicine, University of Miami , Miami , FL , USA.
authors.forename: Eleonore
authors.initials: E
authors.lastname: Beurel
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006380:Helplessness, Learned; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D007438:Introns / Q000187:drug effects*; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000187:drug effects*; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D015854:Up-Regulation
chemical_list: D000928:Antidepressive Agents; D035683:MicroRNAs; C509073:N-myristoyl-glycyl-lysyl-glutamyl-alanyl-prolyl-prolyl-alanyl-prolyl-prolyl-glutaminyl-phosphoseryl-proline; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D044405:Receptor, Serotonin, 5-HT2C; D007649:Ketamine; D038362:Glycogen Synthase Kinase 3
keywords: Ketamine; depression; glycogen synthase kinase-3; hippocampus; microRNA