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The Journal of Neuroscience, October 8, 2003, 23(27):9116-9122

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Cellular/Molecular
Impaired Long-Term Memory and NR2A-Type NMDA Receptor-Dependent Synaptic Plasticity in Mice Lacking c-Fos in the CNS

Alexander Fleischmann,¹ Oivind Hvalby,² Vidar Jensen,² Tatyana Strekalova,³ Christiane Zacher,³ Liliana E. Layer,⁴ Ane Kvello,² Markus Reschke,¹ Rainer Spanagel,³ Rolf Sprengel,⁴ Erwin F. Wagner,¹ and Peter Gass³

¹Research Institute of Molecular Pathology, 1030 Vienna, Austria, ²Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway, ³Central Institute of Mental Health, D-68159 Mannheim, Germany, and ⁴Max Planck Institute for Medical Research, D-69120 Heidelberg, Germany

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-fos^CNS) 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-fos^CNS 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-fos^CNS 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.

Key words: c-fos; NMDA receptor; mice; conditional; behavior; long-term potentiation; hippocampus

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Received April 7, 2003; revised July 18, 2003; accepted July 24, 2003.

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