期刊
WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY
卷 18, 期 6, 页码 445-456出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/15622975.2016.1224927
关键词
Ketamine; glycogen synthase kinase-3; microRNA; depression; hippocampus
类别
资金
- National Institute of Mental Health [MH038752, MH090236, MH104656]
- National Alliance for Research on Schizophrenia and Depression (NARSAD)
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 (10mg/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.
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