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

TLDR

c‑fos, an activator protein‑1 transcription factor, has been implicated in learning and memory mechanisms. The study aimed to test c‑fos’s role in learning by creating CNS‑specific c‑fos knockout mice via Cre‑loxP. CNS‑specific c‑fos deletion was achieved using the Cre‑loxP system. Mice lacking CNS c‑fos displayed normal general behavior yet impaired hippocampal spatial and associative learning, reduced CA3‑CA1 LTP that could be rescued by repeated tetanization but blocked by NR2B inhibition, and evidence that NR2A‑dependent signaling was compromised, underscoring c‑fos’s role in hippocampal learning and NMDA‑dependent LTP.

Abstract

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.