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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Grieco, SF; Velmeshev, D; Magistri, M; Eldar-Finkelman, H; Faghihi, MA; Jope, RS; Beurel, E

Published Date

  • September 2017

Published In

Volume / Issue

  • 18 / 6

Start / End Page

  • 445 - 456

PubMed ID

  • 27723376

Pubmed Central ID

  • PMC5386835

Electronic International Standard Serial Number (EISSN)

  • 1814-1412

Digital Object Identifier (DOI)

  • 10.1080/15622975.2016.1224927

Language

  • eng

Conference Location

  • England