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c-fos regulates neuronal excitability and survival

Nature Genetics volume 30, pages 416–420 (2002)Cite this article

Abstract

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 system1,2,3,4. The immediate early gene (IEG) c-fos encodes a transcription factor5,6. 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 genes7,8,9. Emerging evidence suggests that c-fos is essential in regulating neuronal cell survival versus death10. Although c-fos is induced by neuronal activity, including kainic acid-induced seizures11,12,13,14, 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.

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Figure 1: Generation of f/fc-fos-cre mice.
Figure 2: Basal expression and induction of c-fos is significantly reduced in the hippocampus in f/fc-fos–cre mice.
Figure 3: Kainic acid induces exceptionally severe seizures in the f/fc-fos-cre mouse.
Figure 4: The f/fc-fos-cre mouse shows greater kainic acid–induced neuronal excitability than the wildtype mouse.
Figure 5: The f/fc-fos–cre mouse has a high rate of kainic acid–induced CA3 cell death.
Figure 6: c-fos regulates fosB, GluR6 and BDNF expression in vivo and in vitro.

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Acknowledgements

We are grateful to J. Duffy and M. Yin for mouse blastocyst injections. We thank L. Chen, R. Hennigan, H. Jansen, A. Kuan, H. Lee, D. Lou, M. Privitera, L. Sherman and R. Walsh for various advice, help and discussions. J.Z. and M.X. are supported by grants from the National Institutes of Health, the National Alliance for Research on Schizophrenia and Depression and the Epilepsy Foundation of America. J.S.M. is partially supported by an NIH predoctoral training grant.

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  1. Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, Cincinnati, 45267, Ohio, USA

    Jianhua Zhang, Dongsheng Zhang, Jill Slane McQuade & Ming Xu

  2. Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, 45267, Ohio, USA

    Michael Behbehani

  3. Department of Molecular Biology, Princeton University, Princeton, 08544, New Jersey, USA

    Joe Z. Tsien

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Correspondence to Ming Xu.

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Zhang, J., Zhang, D., McQuade, J. et al. c-fos regulates neuronal excitability and survival. Nat Genet 30, 416–420 (2002). https://doi.org/10.1038/ng859

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