c-fos regulates neuronal excitability and survival

Nat Genet. 2002 Apr;30(4):416-20. doi: 10.1038/ng859. Epub 2002 Mar 4.


Excitotoxicity is a process in which glutamate or other excitatory amino acids induce neuronal cell death. Accumulating evidence suggests that excitotoxicity may contribute to human neuronal cell loss caused by acute insults and chronic degeneration in the central nervous system. The immediate early gene (IEG) c-fos encodes a transcription factor. The c-Fos proteins form heterodimers with Jun family proteins, and the resulting AP-1 complexes regulate transcription by binding to the AP-1 sequence found in many cellular genes. Emerging evidence suggests that c-fos is essential in regulating neuronal cell survival versus death. Although c-fos is induced by neuronal activity, including kainic acid-induced seizures, whether and how c-fos is involved in excitotoxicity is still unknown. To address this issue, we generated a mouse in which c-fos expression is largely eliminated in the hippocampus. We found that these mutant mice have more severe kainic acid-induced seizures, increased neuronal excitability and neuronal cell death, compared with control mice. Moreover, c-Fos regulates the expression of the kainic acid receptor GluR6 and brain-derived neurotrophic factor (BDNF), both in vivo and in vitro. Our results suggest that c-fos is a genetic regulator for cellular mechanisms mediating neuronal excitability and survival.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cell Death
  • Cell Nucleus / metabolism
  • Cell Survival
  • Electroencephalography
  • Excitatory Amino Acid Agonists / pharmacology
  • Gene Expression Regulation
  • Genes, fos / genetics*
  • Genotype
  • Hippocampus / metabolism
  • Immunohistochemistry
  • Kainic Acid / pharmacology
  • Mice
  • Models, Genetic
  • Mutation
  • Neurons / metabolism*
  • Nucleic Acid Hybridization
  • Proto-Oncogene Proteins c-fos / physiology*
  • Receptors, Kainic Acid / biosynthesis
  • Time Factors
  • Transfection


  • Brain-Derived Neurotrophic Factor
  • Excitatory Amino Acid Agonists
  • Gluk2 kainate receptor
  • Proto-Oncogene Proteins c-fos
  • Receptors, Kainic Acid
  • Kainic Acid