Ketamine up-regulates a cluster of intronic miRNAs within the serotonin receptor 2C gene by inhibiting glycogen synthase kinase-3

Steven F. Grieco, Dmitry Velmeshev, Marco Magistri, Hagit Eldar-Finkelman, Mohammad A Faghihi, Richard S Jope, Eleonore Beurel

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Objectives: We examined mechanisms that contribute to the rapid antidepressant effect of ketamine in mice that is dependent on glycogen synthase kinase-3 (GSK3) inhibition. Methods: 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. Results: 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. Conclusions: These findings identify a new outcome of GSK3 inhibition by ketamine that may contribute to antidepressant effects.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalWorld Journal of Biological Psychiatry
DOIs
StateAccepted/In press - Oct 4 2016

Keywords

  • depression
  • glycogen synthase kinase-3
  • hippocampus
  • Ketamine
  • microRNA

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry

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