Constitutive activation of CREB in mice enhances temporal association learning and increases hippocampal CA1 neuronal spine density and complexity.
Constitutive activation of CREB in mice enhances temporal association learning and increases hippocampal CA1 neuronal spine density and complexity.
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DOI：
10.1038/srep42528
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发表时间：
2017-02-14
影响因子：
4.6
通讯作者：
Kida S
中科院分区：
文献类型：
--
作者：
Serita T;Fukushima H;Kida S
转录因子CREB被认为在长期记忆（LTM）的形成中起重要作用，但在学习和短期记忆（STM）中不起作用。令人惊讶的是，我们以前发现，在前脑中表达CREB（DIEDML）显性活性突变体的转基因小鼠（DIEDML小鼠）在依赖于大脑的快速一次性学习任务中表现出增强的STM和LTM。在这里，我们表明，CREB的组成性激活增强了在跟踪恐惧条件反射和延迟匹配到位置任务中的时间关联的海马依赖性学习。然后，我们表明，在DIEDML小鼠海马CA1区锥体神经元的顶端簇树突，所需的时间关联学习，显示增加的棘密度，特别是薄的棘和Homer1阴性棘。与此相反，CA1神经元的基底和顶端斜树突，需要快速的一次试验学习，显示密度增加的薄，蘑菇状，蘑菇棘和Homer1阳性棘。此外，DIEDML小鼠在顶端CA 1树突到索马的近端部分表现出增加的树突复杂性。相反，前脑CaMKIV过表达，导致增强的LTM而不是STM，显示正常的学习和CA1神经元形态。这些结果表明，树突状区域特定的形态学变化CA1神经元组成性激活CREB可能有助于改善学习和STM。
Transcription factor CREB is believed to play essential roles in the formation of long-term memory (LTM), but not in learning and short-term memory (STM). Surprisingly, we previously showed that transgenic mice expressing a dominant active mutant of CREB (DIEDML) in the forebrain (DIEDML mice) demonstrated enhanced STM and LTM in hippocampal-dependent, rapid, one-trial learning tasks. Here we show that constitutive activation of CREB enhances hippocampal-dependent learning of temporal association in trace fear conditioning and delayed matching-to-place tasks. We then show that in DIEDML mice the apical tuft dendrites of hippocampal CA1 pyramidal neurons, required for temporal association learning, display increased spine density, especially of thin spines and of Homer1-negative spines. In contrast, the basal and apical oblique dendrites of CA1 neurons, required for rapid one-trial learning, show increased density of thin, stubby, and mushroom spines and of Homer1-positive spines. Furthermore, DIEDML mice showed increased dendritic complexity in the proximal portion of apical CA1 dendrites to the soma. In contrast, forebrain overexpression of CaMKIV, leading to enhanced LTM but not STM, show normal learning and CA1 neuron morphology. These findings suggest that dendritic region-specific morphological changes in CA1 neurons by constitutive activation of CREB may contribute to improved learning and STM.