Role of glycogen synthase kinase-3beta in early depressive behavior induced by mild traumatic brain injury

Mol Cell Neurosci. 2007 Apr;34(4):571-7. doi: 10.1016/j.mcn.2006.12.006. Epub 2006 Dec 28.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Blotting, Western
  • Brain Injuries / complications*
  • Brain Injuries / enzymology*
  • Depression / enzymology*
  • Depression / etiology*
  • Fluorescent Antibody Technique
  • Glycogen Synthase Kinase 3 / drug effects
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Hippocampus / enzymology
  • Hippocampus / injuries
  • Hippocampus / pathology
  • Lithium Compounds / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Oligopeptides / pharmacology
  • Phosphorylation
  • beta Catenin / metabolism


  • Antidepressive Agents
  • Lithium Compounds
  • N-myristoyl-glycyl-lysyl-glutamyl-alanyl-prolyl-prolyl-alanyl-prolyl-prolyl-glutaminyl-phosphoseryl-proline
  • Oligopeptides
  • beta Catenin
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3