title: Lentivirally mediated GSK-3β silencing in the hippocampal dentate gyrus induces antidepressant-like effects in stressed mice.
abstract: Inhibition of glycogen synthase kinase-3 (GSK-3) by pharmacological tools can produce antidepressant-like effects in rodents. However, the GSK-3 isoform(s) and brain region(s) involved in regulating these behavioural effects remain elusive. We studied the effects of bilateral intra-hippocampal injections of lentivirus-expressing short-hairpin (sh)RNA targeting GSK-3β on behavioural performance in mice subjected to chronic stress. Pre-injection of lentivirus-expressing GSK-3β shRNA into the hippocampal dentate gyrus significantly decreased immobility time in both forced swim and tail suspension tests, while the locomotor activity of these mice was unchanged. These results suggest that lentiviral GSK-3β shRNA injection induces antidepressant-like effects in chronically stressed mice. Under these conditions, the expression levels of GSK-3β were persistently and markedly reduced in the hippocampus following GSK-3β shRNA injection. To our knowledge, this is the first demonstration that a single injection of lentivirus-expressing GSK-3β shRNA in the hippocampal dentate gyrus of chronically stressed mice has antidepressant-like effects elicited by gene silencing.
authors.affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Naoto
authors.initials: N
authors.lastname: Omata
authors.forename: Chi-Tso
authors.initials: CT
authors.lastname: Chiu
authors.forename: Pablo R
authors.initials: PR
authors.lastname: Moya
authors.forename: Yan
authors.initials: Y
authors.lastname: Leng
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Wang
authors.forename: Joshua G
authors.initials: JG
authors.lastname: Hunsberger
authors.forename: Peter
authors.initials: P
authors.lastname: Leeds
authors.forename: De-Maw
authors.initials: DM
authors.lastname: Chuang
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D018891:Dentate Gyrus / Q000502:physiology*; D003891:Desipramine / Q000627:therapeutic use; D005822:Genetic Vectors; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D016086:Lentivirus; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D034741:RNA, Small Interfering / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology*; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D034741:RNA, Small Interfering; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D003891:Desipramine