Abstract
Depression caused by genetic and environmental factors is acomplicated disease. Here, it is demonstrated that glycogen synthase kinase-3β is highly expressed and phosphorylated in the brain of a chronic stress mouse. Inhibition of glycogen synthase kinase-3βleads to decreased depression-like symptoms which manifest in open-field test, tail-suspension test, forced swim test, and a novelty suppressed feeding test. It was also found that β-catenin is attenuated, and its target genes Cyclin D1 and c-Myc are down-regulated. Glycogen synthase kinase-3β was also found to inhibit Erk-Creb-BDNF signaling. These results show that glycogen synthase kinase-3β may promote the progression of depression. Therefore, targeting glycogen synthase kinase-3β may be an effective therapeutic strategy.
Keywords:
BDNF pathway; Gsk3β; Wnt pathway; behavioral testing; chronic stress mouse model; depression.
MeSH terms
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Animals
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Antidepressive Agents / pharmacology
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Brain / enzymology*
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Brain-Derived Neurotrophic Factor / metabolism
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Chronic Disease
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Cyclin D1 / metabolism
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Depressive Disorder / drug therapy
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Depressive Disorder / enzymology*
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Disease Models, Animal
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Feeding Behavior / drug effects
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Feeding Behavior / physiology
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Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
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Glycogen Synthase Kinase 3 beta / metabolism*
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Male
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Mice, Inbred C57BL
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Motor Activity / drug effects
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Motor Activity / physiology
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-myc / metabolism
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RNA, Messenger / metabolism
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Random Allocation
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Stress, Psychological / drug therapy
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Stress, Psychological / enzymology*
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Thiadiazoles / pharmacology
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beta Catenin / metabolism
Substances
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4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione
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Antidepressive Agents
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Brain-Derived Neurotrophic Factor
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Ccnd1 protein, mouse
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Myc protein, mouse
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-myc
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RNA, Messenger
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Thiadiazoles
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beta Catenin
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Cyclin D1
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse