Role of glycogen synthase kinase-3beta in early depressive behavior induced by mild traumatic brain injury.
Traumatic brain injury (TBI) is a triggering event for a set of pathophysiological changes and concomitant depressive behavior. Glycogen synthase kinase-3 (GSK-3) is a potent in vivo regulator of cell apoptosis and, in addition, is implicated in depressive behavior. In this study, we investigated the role of GSK-3 in the physiological model of mild TBI (mTBI) at both the cellular and behavior levels. mTBI resulted in increased phosphorylation of inhibitory site serine(9) of GSK-3beta, which coincided with increased serine(473) phosphorylation of its upstream kinase PKB and accumulation of its downstream target beta-catenin in the hippocampus. mTBI induced a depressive behavior which was evident as early as 24 h post-injury. Pretreatment with GSK-3 inhibitors, lithium, or L803-mts prevented mTBI-induced depression. We suggest that mTBI elicits a pro-survival cascade of PKB/GSK-3beta/beta-catenin as part of a rehabilitation program. Furthermore, the use of selective GSK-3 inhibitors may have therapeutic benefits in treatment conditions associated with brain injury.
Shapira
Moran
M
Department of Molecular Human Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.
Licht
Avital
A
Milman
Anat
A
Pick
Chaim G
CG
Shohami
Esther
E
Eldar-Finkelman
Hagit
H
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D015153:Blotting, Western; D001930:Brain Injuries / Q000150:complications* / Q000201:enzymology*; D003863:Depression / Q000201:enzymology* / Q000209:etiology*; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D018020:Lithium Compounds / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation; D051176:beta Catenin / Q000378:metabolism
D000928:Antidepressive Agents; D018020:Lithium Compounds; C509073:N-myristoyl-glycyl-lysyl-glutamyl-alanyl-prolyl-prolyl-alanyl-prolyl-prolyl-glutaminyl-phosphoseryl-proline; D009842:Oligopeptides; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3