Ketamine up-regulates a cluster of intronic miRNAs within the serotonin receptor 2C gene by inhibiting glycogen synthase kinase-3. (18th August 2017)

• Record Type: Journal Article
• Authors: Grieco, Steven F.; Velmeshev, Dmitry; Magistri, Marco; Eldar-Finkelman, Hagit; Faghihi, Mohammad A.; Jope, Richard S.; Beurel, Eleonore
• Is Part Of: World journal of biological psychiatry. Volume 18:Number 6(2017)
• Page Start: 445
• Page End: 456
• Publication Date: 2017-08-18
• Subjects: Ketamine -- glycogen synthase kinase-3 -- microRNA -- depression -- hippocampus; Biological psychiatry -- Periodicals; Biological Psychiatry -- Periodicals; 616.89
• DOI: 10.1080/15622975.2016.1224927
• Languages: English
• ISSNs: 1562-2975

Abstract

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.