title: Up-regulation of insulin-like growth factor 2 by ketamine requires glycogen synthase kinase-3 inhibition.
abstract: An antidepressant dose of the rapidly-acting ketamine inhibits glycogen synthase kinase-3 (GSK3) in mouse hippocampus, and this inhibition is required for the antidepressant effect of ketamine in learned helplessness depression-like behavior. Here we report that treatment with an antidepressant dose of ketamine (10mg/kg) increased expression of insulin-like growth factor 2 (IGF2) in mouse hippocampus, an effect that required ketamine-induced inhibition of GSK3. Ketamine also inhibited hippocampal GSK3 and increased expression of hippocampal IGF2 in mice when administered after the induction of learned helplessness. Treatment with the specific GSK3 inhibitor L803-mts was sufficient to up-regulate hippocampal IGF2 expression. Administration of IGF2 siRNA reduced ketamine's antidepressant effect in the learned helplessness paradigm. Mice subjected to the learned helplessness paradigm were separated into two groups, those that were resilient (non-depressed) and those that were susceptible (depressed). Non-depressed resilient mice displayed higher expression of IGF2 than susceptible mice. These results indicate that IGF2 contributes to ketamine's antidepressant effect and that IGF2 may confer resilience to depression-like behavior.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, United States.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Grieco
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, United States.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: 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: Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, United States.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Jope
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, United States. Electronic address: ebeurel@med.miami.edu.
authors.forename: Eléonore
authors.initials: E
authors.lastname: Beurel
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006380:Helplessness, Learned; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012727:Sex Characteristics; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000928:Antidepressive Agents; C509073:N-myristoyl-glycyl-lysyl-glutamyl-alanyl-prolyl-prolyl-alanyl-prolyl-prolyl-glutaminyl-phosphoseryl-proline; D009842:Oligopeptides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D007335:Insulin-Like Growth Factor II; D007649:Ketamine; D038362:Glycogen Synthase Kinase 3
keywords: Depression; Glycogen synthase kinase-3; Hippocampus; Insulin-like growth factor 2; Ketamine; Learned helplessness