title: microRNAs as novel antidepressant targets: converging effects of ketamine and electroconvulsive shock therapy in the rat hippocampus.
abstract: Early-life stress is a main contributory factor to the onset of depression. Treatments remain inadequate and as such, a large unmet medical need for novel therapeutics remains. Impeding advancement is the poor understanding of the molecular pathology. microRNAs (miRNAs) are novel regulators of gene expression. A paucity of information regarding their role in depressive pathology and antidepressant action remains. This study investigated changes to hippocampal miRNA levels induced via early-life stress in Sprague-Dawley rats and whether antidepressant treatments could reverse these changes. Investigated were the selective serotonin reuptake inhibitor fluoxetine, the rapid acting N-methyl-d-aspartate receptor antagonist ketamine and electroconvulsive shock therapy (ECT). Microarray analysis revealed early-life stress affected the expression of multiple hippocampal miRNAs. Antidepressant treatments reversed some of these effects including a stress-induced change to miR-451. Ketamine and ECT possessed the highest number of common targets suggesting convergence on common pathways. Interestingly all three treatments possessed miR-598-5p as a common target. This demonstrates that changes to hippocampal miRNA expression may represent an important component of stress-induced pathology and antidepressant action may reverse these.
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Ireland.
authors.forename: Richard M
authors.initials: RM
authors.lastname: O'Connor
authors.forename: Susan
authors.initials: S
authors.lastname: Grenham
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Dinan
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000928:Antidepressive Agents / Q000627:therapeutic use*; D019295:Computational Biology; D003863:Depression / Q000209:etiology / Q000628:therapy*; D004195:Disease Models, Animal; D004565:Electroconvulsive Therapy / Q000379:methods*; D020869:Gene Expression Profiling; D007649:Ketamine / Q000627:therapeutic use*; D008297:Male; D008426:Maternal Deprivation; D035683:MicroRNAs / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats
chemical_list: D000928:Antidepressive Agents; D035683:MicroRNAs; D007649:Ketamine