Inducible cAMP early repressor acts as a negative regulator for kindling epileptogenesis and long-term fear memory
Inducible cAMP early repressor acts as a negative regulator for kindling epileptogenesis and long-term fear memory
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DOI：
10.1523/jneurosci.0412-08.2008
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发表时间：
2008-06-18
影响因子：
5.3
通讯作者：
Endo, Shogo
中科院分区：
文献类型：
--
作者：
Kojima, Nobuhiko;Borlikova, Gilyana;Endo, Shogo
持久的神经元可塑性以及长期记忆（LTM）需要通过基因表达的动态调节重新合成蛋白质。cAMP反应元件（CRE）介导的基因转录以活性依赖性方式发生，并且在多种物种中在神经元可塑性和LTM中起关键作用。为了研究诱导型cAMP早期阻遏物（ICER）在神经元可塑性和LTM中的生理作用，我们产生了两种类型的ICER突变小鼠：ICER过表达（OE）小鼠和ICER特异性敲除（KO）小鼠。ICER-OE和ICER-KO小鼠在发育和生殖方面均未显示出明显的异常。一系列全面的行为测试显示，突变小鼠的运动活动、感觉和运动功能以及情绪反应没有明显变化。然而，长期条件性恐惧记忆在ICER-OE小鼠中减弱，在ICER-KO小鼠中增强，而短期恐惧记忆没有同时发生变化。此外，ICER-OE小鼠表现出点燃发展的延迟，而ICER-KO小鼠表现出点燃的加速。这些结果强烈表明，ICER负调控所需的长期恐惧记忆和神经元可塑性点燃癫痫发生的神经元过程，可能通过抑制CRE-mediated基因转录。
Long-lasting neuronal plasticity as well as long-term memory (LTM) requires de novo synthesis of proteins through dynamic regulation of gene expression. cAMP-responsive element (CRE)-mediated gene transcription occurs in an activity-dependent manner and plays a pivotal role in neuronal plasticity and LTM in a variety of species. To study the physiological role of inducible cAMP early repressor (ICER), a CRE-mediated gene transcription repressor, in neuronal plasticity and LTM, we generated two types of ICER mutant mice: ICER-overexpressing (OE) mice and ICER-specific knock-out (KO) mice. Both ICER-OE and ICER-KO mice show no apparent abnormalities in their development and reproduction. A comprehensive battery of behavioral tests revealed no robust changes in locomotor activity, sensory and motor functions, and emotional responses in the mutant mice. However, long-term conditioned fear memory was attenuated in ICER-OE mice and enhanced in ICER-KO mice without concurrent changes in short-term fear memory. Furthermore, ICER-OE mice exhibited retardation of kindling development, whereas ICER-KO mice exhibited acceleration of kindling. These results strongly suggest that ICER negatively regulates the neuronal processes required for long-term fear memory and neuronal plasticity underlying kindling epileptogenesis, possibly through suppression of CRE-mediated gene transcription.