CRTC1 Function During Memory Encoding Is Disrupted in Neurodegeneration

Abstract

These findings reveal a critical role of CRTC1 in the hippocampus during associative memory, and provide evidence that CRTC1 deregulation underlies memory deficits during neurodegeneration.

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

“…Recent studies suggest important roles for CRTC1 in synaptic plasticity (Kovacs et al, 2007; Zhou et al, 2006) and memory (Hirano et al, 2013; Nonaka et al, 2014; Parra-Damas et al, 2014; Sekeres et al, 2012). Although CRTC1 has been shown to move from the synapse/dendrite to the nucleus in response to neural activity and learning (Ch'ng et al, 2012; Nonaka et al, 2014; Parra-Damas et al, 2016), it remains unclear how CRTC1 acts during memory formation, what shuttling mechanisms are, and how CRTC1 activates target gene transcription independently of CREB phosphorylation.…”

Epigenetic regulation of Fgf1 transcription by CRTC1 and memory enhancement

“…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.…”

“…In the nucleus, CRTC1 increases the expression of a subset of CREB target genes, including c-fos, Arc, Nr4a1, Bdnf (Ch'ng et al, 2012; Fukuchi et al, 2015; Nonaka et al, 2014; Parra-Damas et al, 2017; Parra-Damas et al, 2014; Zhou et al, 2006a) (Fig. 1).…”

“…It is interesting to note that CREB/CRTC1-mediated regulation of gene expression in the hippocampus of a mouse model of Alzheimer’s disease is changed not only in naïve conditions but also in response to learning (Parra-Damas et al, 2014). Moreover, disrupted memory and diminished induction of activity-dependent genes Nr4a1 and Nr4a2 following learning in mice lacking the Alzheimer’s disease-linked presenilin genes (presenilin conditional double knockout mice) are rescued by CRTC1 overexpression in the dorsal hippocampus (Parra-Damas et al, 2017), suggesting an impairment in activity-dependent gene regulation in Alzheimer’s disease. Analysis of human patients shows a reduction of both total and phosphorylated CRTC1 in human hippocampus at Braak IV and V–VI pathological stages of Alzheimer’s disease (Parra-Damas et al, 2014).…”

“…1). 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).…”