H3K9me3 Inhibition Improves Memory, Promotes Spine Formation, and Increases BDNF Levels in the Aged Hippocampus
H3K9me3 Inhibition Improves Memory, Promotes Spine Formation, and Increases BDNF Levels in the Aged Hippocampus
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DOI：
10.1523/jneurosci.2693-15.2016
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发表时间：
2016-03-23
影响因子：
5.3
通讯作者：
Cotman, Carl W.
中科院分区：
文献类型：
--
作者：
Snigdha, Shikha;Prieto, G. Aleph;Cotman, Carl W.
越来越多的研究表明，表观遗传格局的改变可能会导致老年海马体内学习和记忆相关基因的调节受损，最终导致老年大脑的认知缺陷。一个这样的表观遗传抑制标记是H3K9(H3K9me3)的三甲基化，这通常与基因沉默有关。在这里，我们首次确定了H3K9me3及其组蛋白甲基转移酶(SUV39H1)在介导海马记忆功能中的重要作用。使用一种新型和选择性的抑制剂对SUV39H1进行药理抑制可以降低老年小鼠海马区H3K9me3的水平，并改善在目标位置记忆和恐惧条件反射任务以及复杂空间环境学习任务中的表现。抑制SUV39H1可导致老年动物海马区细长而不是蘑菇状的棘突密度增加，以及反映脊椎可塑性的关键指标--海马区突触体内表面GluR1水平的升高。此外，与对照动物相比，药物治疗组动物海马区BDNF外显子I基因启动子发生了变化，与总体BDNF水平一致。综上所述，这些数据表明，SUV39H1抑制和伴随的H3K9me3下调介导了海马区的基因转录，并逆转了海马记忆中年龄相关性的缺陷。
An increasing number of studies show that an altered epigenetic landscape may cause impairments in regulation of learning and memory-related genes within the aged hippocampus, eventually resulting in cognitive deficits in the aged brain. One such epigenetic repressive mark is trimethylation of H3K9 (H3K9me3), which is typically implicated in gene silencing. Here, we identify, for the first time, an essential role for H3K9me3 and its histone methyl transferase (SUV39H1) in mediating hippocampal memory functions. Pharmacological inhibition of SUV39H1 using a novel and selective inhibitor decreased levels of H3K9me3 in the hippocampus of aged mice, and improved performance in the objection location memory and fear conditioning tasks and in a complex spatial environment learning task. The inhibition of SUV39H1 induced an increase in spine density of thin and stubby but not mushroom spines in the hippocampus of aged animals and increased surface GluR1 levels in hippocampal synaptosomes, a key index of spine plasticity. Furthermore, there were changes at BDNF exon I gene promoter, in concert with overall BDNF levels in the hippocampus of drug-treated animals compared with control animals. Together, these data demonstrate that SUV39H1 inhibition and the concomitant H3K9me3 downregulation mediate gene transcription in the hippocampus and reverse age-dependent deficits in hippocampal memory.