HDAC3 is a critical negative regulator of long-term memory formation.
HDAC3 is a critical negative regulator of long-term memory formation.
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DOI：
10.1523/jneurosci.5052-10.2011
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发表时间：
2011-01-12
期刊：
影响因子：
--
通讯作者：
Wood MA
中科院分区：
文献类型：
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作者：
McQuown SC;Barrett RM;Matheos DP;Post RJ;Rogge GA;Alenghat T;Mullican SE;Jones S;Rusche JR;Lazar MA;Wood MA
基因表达受组蛋白尾部染色质修饰的动态调节，如乙酰化。一般来说，组蛋白乙酰化促进转录，而组蛋白去乙酰化负调控转录。组蛋白乙酰转移酶和组蛋白脱乙酰酶之间的相互作用对于调节长期记忆过程所需的基因表达是至关重要的。目前，人们对个体HDAC在学习和记忆中的作用知之甚少。我们用遗传学和药理学相结合的方法研究了HDAC3在长期记忆中的作用。我们使用HDAC3-FLOX转基因小鼠与表达Cre重组酶的腺相关病毒相结合，在背侧海马区CA1区产生局部纯合缺失的HDAC3。为了补充这一方法，我们还使用了HDAC3的选择性抑制剂RGFP 136[N-(6-(2-amino-4-fluorophenylamino)-6-oxohexyl)-4-methylbenzamide].免疫组织化学结果显示，RGFP 136的局灶性缺失或海马区注射导致组蛋白乙酰化增强。HDAC3的局部缺失和通过RGFP 136抑制HDAC3均显著增强了长时记忆。接下来，我们用定量逆转录-聚合酶链式反应检测了与长时记忆有关的基因在背侧海马区的表达。与野生型对照组相比，HDAC3-FLOX小鼠海马区核受体4亚家族A组成员2(Nr4a2)和c-fos的表达显著增加。在HDAC3-FLOX小鼠中观察到的记忆增强被海马区内注射Nr4a2小干扰RNA所消除，这表明HDAC3负面调节记忆形成的机制。综上所述，这些发现表明HDAC3在长期记忆形成的分子机制中发挥了关键作用。
Gene expression is dynamically regulated by chromatin modifications on histone tails, such as acetylation. In general, histone acetylation promotes transcription, whereas histone deacetylation negatively regulates transcription. The interplay between histone acetyl-transerases and histone deacetylases (HDACs) is pivotal for the regulation of gene expression required for long-term memory processes. Currently, very little is known about the role of individual HDACs in learning and memory. We examined the role of HDAC3 in long-term memory using a combined genetic and pharmacologic approach. We used HDAC3–FLOX genetically modified mice in combination with adeno-associated virus-expressing Cre recombinase to generate focal homozygous deletions of Hdac3 in area CA1 of the dorsal hippocampus. To complement this approach, we also used a selective inhibitor of HDAC3, RGFP136 [N-(6-(2-amino-4-fluorophenylamino)-6-oxohexyl)-4-methylbenzamide]. Immunohistochemistry showed that focal deletion or intrahippocampal delivery of RGFP136 resulted in increased histone acetylation. Both the focal deletion of HDAC3 as well as HDAC3 inhibition via RGFP136 significantly enhanced long-term memory in a persistent manner. Next we examined expression of genes implicated in long-term memory from dorsal hippocampal punches using quantitative reverse transcription-PCR. Expression of nuclear receptor subfamily 4 group A, member 2 (Nr4a2) and c-fos was significantly increased in the hippocampus of HDAC3–FLOX mice compared with wild-type controls. Memory enhancements observed in HDAC3–FLOX mice were abolished by intrahippocampal delivery of Nr4a2 small interfering RNA, suggesting a mechanism by which HDAC3 negatively regulates memory formation. Together, these findings demonstrate a critical role for HDAC3 in the molecular mechanisms underlying long-term memory formation.