Abstract:
Memory engrams are a subset of learning activated neurons critical for memory recall, consolidation, extinction and separation. While the transcriptional profile of engrams after learning suggests profound neural changes underlying plasticity and memory formation, little is known about how memory engrams are selected and allocated. As epigenetic factors suppress memory formation, we developed a CRISPR screening in the hippocampus to search for factors controlling engram formation. We identified histone lysine-specific demethylase 4a (Kdm4a) as a negative regulator for engram formation. Kdm4a is downregulated after neural activation and controls the volume of mossy fiber boutons. Mechanistically, Kdm4a anchors to the exonic region of Trpm7 gene loci, causing the stalling of nascent RNAs and allowing burst transcription of Trpm7 upon the dismissal of Kdm4a. Furthermore, the YTH domain containing protein 2 (Ythdc2) recruits Kdm4a to the Trpm7 gene and stabilizes nascent RNAs. Reducing the expression of Kdm4a in the hippocampus via genetic manipulation or artificial neural activation facilitated the ability of pattern separation in rodents. Our work indicates that Kdm4a is a negative regulator of engram formation and suggests a priming state to generate a separate memory.
摘要:
记忆图是对记忆回忆至关重要的学习激活神经元的子集,合并,灭绝和分离。虽然学习后的转录谱表明可塑性和记忆形成背后的深刻神经变化,关于如何选择和分配内存语法知之甚少。由于表观遗传因素抑制记忆形成,我们在海马区进行了CRISPR筛查,以寻找控制印迹形成的因素.我们确定了组蛋白赖氨酸特异性脱甲基酶4a(Kdm4a)作为印迹形成的负调节因子。Kdm4a在神经激活后下调,并控制苔藓纤维束的体积。机械上,Kdm4a锚定到Trpm7基因位点的外显子区,引起新生RNA的停滞,并在Kdm4a被解雇时允许Trpm7的爆发转录。此外,含YTH域的蛋白2(Ythdc2)将Kdm4a募集到Trpm7基因并稳定新生的RNA。通过遗传操作或人工神经激活减少海马中Kdm4a的表达有助于啮齿动物的模式分离能力。我们的工作表明,Kdm4a是印迹形成的负调节剂,并提出了一个启动状态来产生单独的记忆。