CRTC1 Nuclear Translocation Following Learning Modulates Memory Strength via Exchange of Chromatin Remodeling Complexes on the Fgf1 Gene

Abstract

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 factor 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.

Epigenetic regulation of Fgf1 transcription by CRTC1 and memory enhancement

“…Both the focal deletion of HDAC3 in the CA subregion of hippocampus as well as HDAC3 inhibition via RGFP136 significantly enhances long-term memory (McQuown et al, 2011). Similarly, viral-mediated acute knockdown of HDAC3 in the CA subregion of the hippocampus or intra-hippocampal injection of an HDAC3 selective inhibitor leads to enhanced contextual fear memory (Uchida et al, 2017a). However, a prolonged HDAC3 depletion reduces memory (Nott et al, 2016).…”

“…A recent paper has shown that KAT5 (also referred to as Tip60) plays a key role in learning-induced histone H4K12 acetylation, a potentially important lysine residue of histone H4 for memory (Guan et al, 2009; Peleg et al, 2010), and this mechanism is important for regulation of memory enhancement (Uchida et al, 2017a). …”

“…A recent report has shown that two phosphorylation sites (S151 and S245) contribute to nuclear import of CRTC1 (Nonaka et al, 2014). The nuclear transport of CRTC1 is observed in the CA1 and CA3 pyramidal neurons, but not in the dentate gyrus granule neurons, of the hippocampus following multiple behavioral tasks, including contextual fear conditioning (CFC), novel object location and Morris water maze (Parra-Damas et al, 2017; Uchida and Shumyatsky, 2017; Uchida et al, 2017a). Importantly, strong training of CFC induces much greater CRTC1 nuclear accumulation than weak CFC training (Uchida et al, 2017a), suggesting an association of CRTC1 nuclear translocation with memory strength.…”

“…CRTC1 is translocated from the synapses/dendrites to the nucleus in response to neural activity and learning (Ch'ng et al, 2012; Kovacs et al, 2007; Li et al, 2009; Nonaka et al, 2014; Parra-Damas et al, 2017; Uchida et al, 2017a). Some reports have shown recently that CRTC1 plays a key role in synaptic plasticity and memory formation in rodents (Nonaka et al, 2014; Sekeres et al, 2012; Uchida et al, 2017a; Zhou et al, 2006a). Moreover, CRTC1 is associated with memory enhancement and memory maintenance via epigenetic regulation of gene transcription (Hirano et al, 2016; Uchida and Shumyatsky, 2017; Uchida et al, 2017a).…”

“…Some reports have shown recently that CRTC1 plays a key role in synaptic plasticity and memory formation in rodents (Nonaka et al, 2014; Sekeres et al, 2012; Uchida et al, 2017a; Zhou et al, 2006a). Moreover, CRTC1 is associated with memory enhancement and memory maintenance via epigenetic regulation of gene transcription (Hirano et al, 2016; Uchida and Shumyatsky, 2017; Uchida et al, 2017a). …”