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The Journal of Neuroscience, September 1, 1998, 18(17):6952-6962

Essential Role of the fosB Gene in Molecular, Cellular, and Behavioral Actions of Chronic Electroconvulsive Seizures

Noboru Hiroi¹, Gerard J. Marek¹, Jennifer R. Brown², Hong Ye², Frederic Saudou², Vidita A. Vaidya¹, Ronald S. Duman¹, Michael E. Greenberg², and Eric J. Nestler¹

¹ Laboratory of Molecular Psychiatry, Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06508, and ² Division of Neuroscience, Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115

The role of Fos-like transcription factors in neuronal and behavioral plasticity has remained elusive. Here we demonstrate that a Fos family member protein plays physiological roles in the neuronal, electrophysiological, and behavioral plasticity associated with repeated seizures. Repeated electroconvulsive seizures (ECS) induced isoforms of FosB in frontal cortex, an effect that was associated with increased levels of the NMDA receptor 1 (NMDAR1) glutamate receptor subunit. Induction of FosB and the upregulation of NMDAR1 occurred within the same neurons in superficial layers of neocortex. Activator protein-1 (AP-1) complexes composed of FosB were bound to a consensus AP-1 site in the 5'-promoter region of the NMDAR1 gene. The upregulation of NMDAR1 was absent in mice with a targeted disruption of the fosB gene. In addition, repeated ECS treatment caused progressively shorter motor seizures (tolerance) in both rats and wild-type mice, as well as reduced NMDA-induced inward currents in pyramidal neurons from superficial layers of the neocortex of wild-type mice. These behavioral and electrophysiological effects were also significantly attenuated in fosB mutant mice. These findings identify fosB gene products as transcription factors critical for molecular, electrophysiological, and behavioral adaptations to motor seizures.

Key words: transcription factor; seizure; ECS; cerebral cortex; c-Fos; FosB; FosB; FRA; JunD; AP-1; neural plasticity; depression; epilepsy; NMDA receptor

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18176952-11$05.00/0

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