Impaired long-term memory and NR2A-type NMDA receptor-dependent synaptic plasticity in mice lacking c-Fos in the CNS

J Neurosci. 2003 Oct 8;23(27):9116-22. doi: 10.1523/JNEUROSCI.23-27-09116.2003.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / genetics
  • Behavior, Animal
  • Central Nervous System / metabolism
  • Central Nervous System / physiopathology*
  • Conditioning, Psychological
  • Cues
  • Electric Stimulation
  • Excitatory Postsynaptic Potentials
  • Gene Targeting / methods
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • In Vitro Techniques
  • Long-Term Potentiation / genetics
  • Maze Learning
  • Memory Disorders / genetics
  • Memory Disorders / physiopathology*
  • Mice
  • Mice, Knockout
  • Motor Activity / genetics
  • Neuronal Plasticity / genetics
  • Neuronal Plasticity / physiology*
  • Organ Specificity
  • Proto-Oncogene Proteins c-fos / deficiency*
  • Proto-Oncogene Proteins c-fos / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Signal Transduction
  • Synapses / metabolism
  • Time


  • NR2A NMDA receptor
  • NR2B NMDA receptor
  • Proto-Oncogene Proteins c-fos
  • Receptors, N-Methyl-D-Aspartate