Essential role of the fosB gene in molecular, cellular, and behavioral actions of chronic electroconvulsive seizures.
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 DeltaFosB in frontal cortex, an effect that was associated with increased levels of the NMDA receptor 1 (NMDAR1) glutamate receptor subunit. Induction of DeltaFosB and the upregulation of NMDAR1 occurred within the same neurons in superficial layers of neocortex. Activator protein-1 (AP-1) complexes composed of DeltaFosB 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.
Laboratory of Molecular Psychiatry, Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
N
N
Hiroi
G J
GJ
Marek
J R
JR
Brown
H
H
Ye
F
F
Saudou
V A
VA
Vaidya
R S
RS
Duman
M E
ME
Greenberg
E J
EJ
Nestler
D000223:Adaptation, Psychological; D000818:Animals; D002908:Chronic Disease; D004597:Electroshock; D005625:Frontal Lobe / Q000166:cytology / Q000502:physiology; D016762:Genes, fos; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D019579:Neocortex / Q000166:cytology / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D012640:Seizures / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000235:genetics*
D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; D018808:Transcription Factor AP-1