ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning
ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning
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DOI：
10.1101/lm.152906
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发表时间：
2006-05-01
影响因子：
2
通讯作者：
Sweatt, J. David
中科院分区：
文献类型：
--
作者：
Chwang, Wilson B.;O'Riordan, Kenneth J.;Sweatt, J. David
长期记忆的形成受到许多不同的分子机制的调控，这些机制控制着基因的表达。一种影响稳定、协调的基因转录模式的新模式涉及通过修饰组蛋白或DNA进行表观遗传标记。在这项研究中，我们研究了ERK/MAPK（细胞外信号调节激酶/丝裂原活化蛋白激酶）途径对海马组蛋白磷酸化的调控。我们发现ERK/MAPK在体外激活显著增加海马区CA1的组蛋白H3磷酸化。此外，我们发现体内情境恐惧条件反射导致CA1区组蛋白H3磷酸化的快速时间依赖性增加。这种增加与情境恐惧依赖的ERK激活的时间过程平行，并且在体内被潜在抑制范式和注射n -甲基-d -天冬氨酸受体（NMDA-R）拮抗剂抑制。最后，注射MEK （MAP激酶/ERK激酶）抑制剂（ERK上游独特的双特异性激酶）阻断了情境恐惧条件反射后组蛋白H3磷酸化的增加。这些结果表明，海马组蛋白磷酸化的变化受ERK/MAPK的调节，并遵循行为恐惧条件反射模式。
Long-term memory formation is regulated by many distinct molecular mechanisms that control gene expression. An emerging model for effecting a stable, coordinated pattern of gene transcription involves epigenetic tagging through modifications of histones or DNA. In this study, we investigated the regulation of histone phosphorylation in the hippocampus by the ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) pathway. We found that activation of ERK/MAPK in vitro significantly increased histone H3 phosphorylation in hippocampal area CA1. Furthermore, we found that contextual fear conditioning in vivo leads to a rapid time-dependent increase in histone H3 phosphorylation in area CA1. This increase paralleled the time course of contextual fear-dependent activation of ERK, and was inhibited in vivo by a latent inhibition paradigm as well as by injection of an N-methyl-D-aspartic acid receptor (NMDA-R) antagonist. Finally, injection of an inhibitor of MEK (MAP kinase/ERK kinase), the unique dual-specificity kinase upstream of ERK, blocked the increase in histone H3 phosphorylation seen after contextual fear conditioning. These results demonstrate that changes in histone phosphorylation in the hippocampus are regulated by ERK/MAPK following a behavioral fear conditioning paradigm.