c-fos regulates neuronal excitability and survival.
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.
Zhang
Jianhua
J
Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Zhang
Dongsheng
D
McQuade
Jill Slane
JS
Behbehani
Michael
M
Tsien
Joe Z
JZ
Xu
Ming
M
D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D004569:Electroencephalography; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation; D016762:Genes, fos / Q000235:genetics*; D005838:Genotype; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D008957:Models, Genetic; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D009693:Nucleic Acid Hybridization; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology*; D018092:Kainic Acid Receptors / Q000096:biosynthesis; D013997:Time Factors; D014162:Transfection; D000097806:GluK2 Kainate Receptor
D019208:Brain-Derived Neurotrophic Factor; D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid; D016760:Proto-Oncogene Proteins c-fos; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor