Cell Reports
Volume 18, Issue 2, 10 January 2017, Pages 352-366
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Article
CRTC1 Nuclear Translocation Following Learning Modulates Memory Strength via Exchange of Chromatin Remodeling Complexes on the Fgf1 Gene

https://doi.org/10.1016/j.celrep.2016.12.052Get rights and content
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Highlights

  • Neuronal stimulation and learning induce Fgf1b in the mouse hippocampus

  • FGF1 is essential for enduring long-term potentiation and memory enhancement

  • Learning-induced nuclear transport of CRTC1 activates Fgf1b transcription

  • CRTC1-mediated substitution of KAT5 for CBP on the Fgf1b promoter enhances memory

Summary

Memory is formed by synapse-to-nucleus communication that leads to regulation of gene transcription, but the identity and organizational logic of signaling pathways involved in this communication remain unclear. Here we find that the transcription cofactor CRTC1 is a critical determinant of sustained gene transcription and memory strength in the hippocampus. Following associative learning, synaptically localized CRTC1 is translocated to the nucleus and regulates Fgf1b transcription in an activity-dependent manner. After both weak and strong training, the HDAC3-N-CoR corepressor complex leaves the Fgf1b promoter and a complex involving the translocated CRTC1, phosphorylated CREB, and histone acetyltransferase CBP induces transient transcription. Strong training later substitutes KAT5 for CBP, a process that is dependent on CRTC1, but not on CREB phosphorylation. This in turn leads to long-lasting Fgf1b transcription and memory enhancement. Thus, memory strength relies on activity-dependent changes in chromatin and temporal regulation of gene transcription on specific CREB/CRTC1 gene targets.

Keywords

memory enhancement
long-term potentiation
hippocampus
nuclear transport
epigenetics
FGF1
CRTC1
KAT5/Tip60
HDAC3
CREB

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