title: CRTC1 Nuclear Translocation Following Learning Modulates Memory Strength via Exchange of Chromatin Remodeling Complexes on the Fgf1 Gene.
abstract: 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.
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan; Department of Genetics, Rutgers University, 145 Bevier Road, Piscataway, NJ 08854, USA. Electronic address: s-uchida@yamaguchi-u.ac.jp.
authors.forename: Shusaku
authors.initials: S
authors.lastname: Uchida
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Brett J W
authors.initials: BJW
authors.lastname: Teubner
authors.affiliation: Department of Genetics, Rutgers University, 145 Bevier Road, Piscataway, NJ 08854, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Hevi
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hara
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kobayashi
authors.affiliation: Department of Genetics, Rutgers University, 145 Bevier Road, Piscataway, NJ 08854, USA.
authors.forename: Rutu M
authors.initials: RM
authors.lastname: Dave
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Shintaku
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan.
authors.forename: Pattaporn
authors.initials: P
authors.lastname: Jaikhan
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Yamagata
authors.affiliation: Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan; Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Stanislav S
authors.initials: SS
authors.lastname: Zakharenko
authors.affiliation: Department of Genetics, Rutgers University, 145 Bevier Road, Piscataway, NJ 08854, USA. Electronic address: gleb@biology.rutgers.edu.
authors.forename: Gleb P
authors.initials: GP
authors.lastname: Shumyatsky
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D044127:Epigenesis, Genetic; D016220:Fibroblast Growth Factor 1 / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D017774:Long-Term Potentiation / Q000235:genetics; D000074443:Lysine Acetyltransferase 5 / Q000378:metabolism; D008297:Male; D008568:Memory; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D021381:Protein Transport; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics; D000099186:Histone Deacetylase 3
chemical_list: D019703:Calcineurin; D016220:Fibroblast Growth Factor 1; D006655:Histone Deacetylases; D000074443:Lysine Acetyltransferase 5; D015534:Trans-Activators; D014157:Transcription Factors; D000099186:Histone Deacetylase 3; C519509:Crtc1 protein, mouse; C523065:Kat5 protein, mouse
keywords: CREB; CRTC1; FGF1; HDAC3; KAT5/Tip60; epigenetics; hippocampus; long-term potentiation; memory enhancement; nuclear transport