Region-Specific Activation of CRTC1-CREB Signaling Mediates Long-Term Fear Memory
Region-Specific Activation of CRTC1-CREB Signaling Mediates Long-Term Fear Memory
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DOI：
10.1016/j.neuron.2014.08.049
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发表时间：
2014-10-01
期刊：
影响因子：
16.2
通讯作者：
Bito, Haruhiko
中科院分区：
文献类型：
--
作者：
Nonaka, Mio;Kim, Ryang;Bito, Haruhiko
CREB是活动调节基因转录的关键介质，是记忆形成和分配的基础。然而，CREB关键辅助因子，CREB调节的转录辅助因子1 （CRTC1）的作用仍然难以捉摸。在这里，我们发现几种构成激酶途径和一种活性调节的磷酸酶钙调磷酸酶聚集在一起决定CRTC1的核胞质穿梭。这反过来又触发了CRTC1与IEG启动子上发现的creb依赖性调控元件的活性依赖性关联。海马神经元中核CRTC1的强制表达激活了creb依赖性转录，足以增强情境恐惧记忆。令人惊讶的是，在情境恐惧条件反射过程中，我们发现内源性CRTC1的核募集仅在杏仁核基底外侧，而不是在海马体中。与此一致的是，在杏仁核中，而在海马体中，CRTC1基因的敲除显著减弱了恐惧记忆。因此，CRTC1对依赖CREB的记忆过程有广泛的影响，但以特定区域的方式微调CREB输出。
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.