Lentivirally mediated GSK-3β silencing in the hippocampal dentate gyrus induces antidepressant-like effects in stressed mice.
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.
Omata
Naoto
N
Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Chiu
Chi-Tso
CT
Moya
Pablo R
PR
Leng
Yan
Y
Wang
Zhifei
Z
Hunsberger
Joshua G
JG
Leeds
Peter
P
Chuang
De-Maw
DM
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
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