Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3

Vesa Hongisto, Nina Smeds, Stephan Brecht, Thomas Herdegen, Michael J Courtney, Eleanor T Coffey

Research output: Contribution to journalArticleScientificpeer-review

132 Citations (Scopus)


Lithium has been used as an effective mood-stabilizing drug for the treatment of manic episodes and depression for 50 years. More recently, lithium has been found to protect neurons from death induced by a wide array of neurotoxic insults. However, the molecular basis for the prophylactic effects of lithium have remained obscure. A target of lithium, glycogen synthase kinase 3 (GSK-3), is implicated in neuronal death after trophic deprivation. The mechanism whereby GSK-3 exerts its neurotoxic effects is also unknown. Here we show that lithium blocks the canonical c-Jun apoptotic pathway in cerebellar granule neurons deprived of trophic support. This effect is mimicked by the structurally independent inhibitors of GSK-3, FRAT1, and indirubin. Like lithium, these prevent the stress induced c-Jun protein increase and subsequent apoptosis. These events are downstream of c-Jun transactivation, since GSK-3 inhibitors block neuronal death induced by constitutively active c-Jun (Ser/Thr-->Asp) and FRAT1 expression inhibits AP1 reporter activity. Consistent with this, AP1-dependent expression of proapoptotic Bim requires GSK-3-like activity. These data suggest that a GSK-3-like kinase acts in tandem with c-Jun N-terminal kinase to coordinate the full execution of the c-Jun stress response and neuronal death in response to trophic deprivation.

Original languageEnglish
Pages (from-to)6027-36
Number of pages10
JournalMolecular and Cellular Biology
Issue number17
Publication statusPublished - Sept 2003
MoE publication typeA1 Journal article-refereed


  • Adaptor Proteins, Signal Transducing
  • Animals
  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • Carrier Proteins/drug effects
  • Cell Death/drug effects
  • Cells, Cultured
  • Cerebellum/cytology
  • Dose-Response Relationship, Drug
  • Enzyme Activation/drug effects
  • Genes, Reporter
  • Glycogen Synthase Kinase 3/drug effects
  • Indoles/pharmacology
  • JNK Mitogen-Activated Protein Kinases
  • Lithium/pharmacology
  • Membrane Proteins
  • Mice
  • Mice, Mutant Strains
  • Mitogen-Activated Protein Kinases/drug effects
  • Neoplasm Proteins
  • Neurons/drug effects
  • Neuroprotective Agents/pharmacology
  • Oximes/pharmacology
  • Phosphoric Monoester Hydrolases/drug effects
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins/genetics
  • Rats
  • Stress, Physiological
  • Transcription Factor AP-1/genetics
  • Up-Regulation


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