TY - JOUR
T1 - Region-Specific Activation of CRTC1-CREB Signaling Mediates Long-Term Fear Memory
AU - Nonaka, Mio
AU - Kim, Ryang
AU - Fukushima, Hotaka
AU - Sasaki, Kazuki
AU - Suzuki, Kanzo
AU - Okamura, Michiko
AU - Ishii, Yuichiro
AU - Kawashima, Takashi
AU - Kamijo, Satoshi
AU - Takemoto-Kimura, Sayaka
AU - Okuno, Hiroyuki
AU - Kida, Satoshi
AU - Bito, Haruhiko
N1 - Funding Information:
We thank J.-P. Bellier and H. Kimura (Shiga University of Medical Science) as well as S. Josselyn and P. Frankland (Hospital for Sick Children, Toronto) for invaluable advice during the precursory phase of this study; C. Vinson (NIH) for an A-CREB vector; H. Hioki and T. Kaneko (Kyoto University) for the lentiviral vectors; R. Kotin (NIH), B. Davidson (University of Iowa), and I. Bezprozvanny (UTSW) for access to original AAV vectors; T. Curran (University of Pennsylvania) for c-fos promoter; A. Tabuchi and M. Tsuda (Toyama University) for BDNF promoter IV; Y. Ishihama, N. Sugiyama (Kyoto University), and H. Nakatsumi (Kyushu University) for advice on LC-MS/MS; R. Morris (University of Edinburgh), L. Monteggia (UTSW), V. Ramirez-Amaya (Autonomous University of Queretaro), and P. Cohen (University of Dundee) for discussion on an early version of the work; all members of the Bito and Kida laboratories for support and discussion; and A. Adachi-Morishima, Y. Kondo, K. Saiki, R. Gyobu, Y. Dobashi, and T. Kinbara for assistance. This work was supported in part by Grants-in-Aid from MEXT and JSPS (to M.N., K. Sasaki, M.O., S.T.-K., H.O., S. Kida, and H.B.), by CREST-JST (to S. Kida and H.B.), by a JST-CONACyT SICP grant (to H.O. and H.B.), by awards from the Yamada Science Foundation , the Mitsubishi Foundation , the Takeda Science Foundation , and the Uehara Memorial Foundation (to H.B.), and from The Tokyo Society of Medical Sciences (to H.O.). K. Suzuki, Y.I., S. Kamijo, and T.K. were predoctoral fellows of the JSPS.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.neuron.2014.08.049
DO - 10.1016/j.neuron.2014.08.049
M3 - Article
C2 - 25277455
AN - SCOPUS:84908007671
VL - 84
SP - 92
EP - 106
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 1
ER -