NMDA receptor- and ERK-dependent histone methylation changes in the lateral amygdala bidirectionally regulate fear memory formation.
NMDA receptor- and ERK-dependent histone methylation changes in the lateral amygdala bidirectionally regulate fear memory formation.
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DOI：
10.1101/lm.035105.114
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发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
Lubin FD
中科院分区：
文献类型：
--
作者：
Gupta-Agarwal S;Jarome TJ;Fernandez J;Lubin FD
众所周知，恐惧记忆的形成需要杏仁核的从头基因转录。我们提供的证据表明，杏仁外侧核(LA)组蛋白赖氨酸甲基化的表观遗传机制受NMDAR信号调节，并参与恐惧记忆巩固所需的基因转录变化。在这里，我们发现组蛋白H3赖氨酸9二甲基化(H3K9me2)水平在听觉恐惧条件作用后1h在LA中增加，并持续到行为训练后25h。此外，我们还证明了抑制LA中的H3K9me2组蛋白赖氨酸甲基转移酶G9a(H/KMTs-G9a)会损害恐惧记忆，而阻断H3K9me2组蛋白赖氨酸去甲基酶LSD1(H/KDM-LSD1)会增强恐惧记忆，提示LA中的H3K9me2可以双向调节恐惧记忆的形成。此外，我们还发现，NMDAR活性对H/KMT-G9a、H/KDM-LSD1和随后的H3K9me2水平在靶基因启动子上的招募有不同的调节作用。这在很大程度上是由含有GluN2B的NMDAR通过ERK激活来调节的，而不是GluN2A。此外，与NMDAR或ERK阻断相关的恐惧记忆缺陷可以通过药物抑制LSD1成功地修复，这表明增强LA内H3K9me2的水平可以修复由于NMDAR功能低下或ERK信号丢失而造成的恐惧记忆障碍。综上所述，本研究表明，组蛋白赖氨酸甲基化调节通过NMDAR-ERK依赖的信号通路参与恐惧记忆的形成。
It is well established that fear memory formation requires de novo gene transcription in the amygdala. We provide evidence that epigenetic mechanisms in the form of histone lysine methylation in the lateral amygdala (LA) are regulated by NMDA receptor (NMDAR) signaling and involved in gene transcription changes necessary for fear memory consolidation. Here we found increases in histone H3 lysine 9 dimethylation (H3K9me2) levels in the LA at 1 h following auditory fear conditioning, which continued to be temporally regulated up to 25 h following behavioral training. Additionally, we demonstrate that inhibiting the H3K9me2 histone lysine methyltransferase G9a (H/KMTs-G9a) in the LA impaired fear memory, while blocking the H3K9me2 histone lysine demethylase LSD1 (H/KDM-LSD1) enhanced fear memory, suggesting that H3K9me2 in the LA can bidirectionally regulate fear memory formation. Furthermore, we show that NMDAR activity differentially regulated the recruitment of H/KMT-G9a, H/KDM-LSD1, and subsequent H3K9me2 levels at a target gene promoter. This was largely regulated by GluN2B- but not GluN2A-containing NMDARs via ERK activation. Moreover, fear memory deficits associated with NMDAR or ERK blockade were successfully rescued through pharmacologically inhibiting LSD1, suggesting that enhancements of H3K9me2 levels within the LA can rescue fear memory impairments that result from hypofunctioning NMDARs or loss of ERK signaling. Together, the present study suggests that histone lysine methylation regulation in the LA via NMDAR-ERK-dependent signaling is involved in fear memory formation.
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DOI：
10.1523/jneurosci.4022-09.2010
发表时间：
2010-02-17
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Foster KA;McLaughlin N;Edbauer D;Phillips M;Bolton A;Constantine-Paton M;Sheng M
通讯作者：
Sheng M
影响因子：
1.9
作者：
Bailey, DJ;Kim, JJ;Helmstetter, FJ
通讯作者：
Helmstetter, FJ
影响因子：
5.3
作者：
Bauer, EP;Schafe, GE;LeDoux, JE
通讯作者：
LeDoux, JE
影响因子：
4.8
作者：
Levenson, Jonathan M.;Roth, Tania L.;Sweatt, J. David
通讯作者：
Sweatt, J. David
影响因子：
15
作者：
Binda, Claudia;Valente, Sergio;Mai, Antonello
通讯作者：
Mai, Antonello