title: Region-specific activation of CRTC1-CREB signaling mediates long-term fear memory.
abstract: CREB is a pivotal mediator of activity-regulated gene transcription that underlies memory formation and allocation. The contribution of a key CREB cofactor, CREB-regulated transcription coactivator 1 (CRTC1), has, however, remained elusive. Here we show that several constitutive kinase pathways and an activity-regulated phosphatase, calcineurin, converge to determine the nucleocytoplasmic shuttling of CRTC1. This, in turn, triggered an activity-dependent association of CRTC1 with CREB-dependent regulatory elements found on IEG promoters. Forced expression of nuclear CRTC1 in hippocampal neurons activated CREB-dependent transcription, and was sufficient to enhance contextual fear memory. Surprisingly, during contextual fear conditioning, we found evidence of nuclear recruitment of endogenous CRTC1 only in the basolateral amygdala, and not in the hippocampus. Consistently, CRTC1 knockdown in the amygdala, but not in the hippocampus, significantly attenuated fear memory. Thus, CRTC1 has a wide impact on CREB-dependent memory processes, but fine-tunes CREB output in a region-specific manner.
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; CREST-JST, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Mio
authors.initials: M
authors.lastname: Nonaka
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; CREST-JST, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Ryang
authors.initials: R
authors.lastname: Kim
authors.affiliation: Department of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan.
authors.forename: Hotaka
authors.initials: H
authors.lastname: Fukushima
authors.affiliation: Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Sasaki
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; CREST-JST, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Kanzo
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Okamura
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; CREST-JST, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawashima
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; CREST-JST, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kamijo
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; PRESTO-JST, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Takemoto-Kimura
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; CREST-JST, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okuno
authors.affiliation: Department of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan; CREST-JST, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kida
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; CREST-JST, Chiyoda-ku, Tokyo 102-0076, Japan. Electronic address: hbito@m.u-tokyo.ac.jp.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Bito
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005239:Fear / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009474:Neurons / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C492004:Creb1 protein, mouse; C519509:Crtc1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors