Impaired long-term memory and NR2A-type NMDA receptor-dependent synaptic plasticity in mice lacking c-Fos in the CNS.
The immediate early gene c-fos is part of the activator protein-1 transcription factor and has been postulated to participate in the molecular mechanisms of learning and memory. To test this hypothesis in vivo, we generated mice with a nervous system-specific c-fos knock-out using the Cre-loxP system. Adult mice lacking c-Fos in the CNS (c-fosDeltaCNS) showed normal general and emotional behavior but were specifically impaired in hippocampus-dependent spatial and associative learning tasks. These learning deficits correlated with a reduction of long-term potentiation (LTP) in hippocampal CA3-CA1 synapses. The magnitude of LTP was restored by a repeated tetanization procedure, suggesting impaired LTP induction in c-fosDeltaCNS mice. This rescue was blocked by a selective inhibitor of NR2B-type NMDA receptors. This blockade was compensated in wild-type mice by NR2A-type NMDA receptor-activated signaling pathways, thus indicating that these pathways are compromised in c-fosDeltaCNS mice. In summary, our data suggest a role for c-Fos in hippocampus-dependent learning and memory as well as in NMDA receptor-dependent LTP formation.
Fleischmann
Alexander
A
Research Institute of Molecular Pathology, 1030 Vienna, Austria.
Hvalby
Oivind
O
Jensen
Vidar
V
Strekalova
Tatyana
T
Zacher
Christiane
C
Layer
Liliana E
LE
Kvello
Ane
A
Reschke
Markus
M
Spanagel
Rainer
R
Sprengel
Rolf
R
Wagner
Erwin F
EF
Gass
Peter
P
D000818:Animals; D001007:Anxiety / Q000235:genetics; D001522:Behavior, Animal; D002490:Central Nervous System / Q000378:metabolism / Q000503:physiopathology*; D003213:Conditioning, Psychological; D003463:Cues; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials; D018390:Gene Targeting / Q000379:methods; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000235:genetics; D018782:Maze Learning; D008569:Memory Disorders / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D009928:Organ Specificity; D016760:Proto-Oncogene Proteins c-fos / Q000172:deficiency* / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism; D013995:Time
C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate