Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, 92037, USA.
The Dorris Neuroscience Center and The Scripps Research Institute, La Jolla, CA, 92037, USA.
Nat Commun. 2019 Aug 2;10(1):3469. doi: 10.1038/s41467-019-11409-0.
The formation of new memories requires transcription. However, the mechanisms that limit signaling of relevant gene programs in space and time for precision of information coding remain poorly understood. We found that, during learning, the cellular patterns of expression of early response genes (ERGs) are regulated by class IIa HDACs 4 and 5, transcriptional repressors that transiently enter neuronal nuclei from cytoplasm after sensory input. Mice lacking these repressors in the forebrain have abnormally broad experience-dependent expression of ERGs, altered synaptic architecture and function, elevated anxiety, and severely impaired memory. By acutely manipulating the nuclear activity of class IIa HDACs in behaving animals using a chemical-genetic technique, we further demonstrate that rapid induction of transcriptional programs is critical for memory acquisition but these programs may become dispensable when a stable memory is formed. These results provide new insights into the molecular basis of memory storage.
新记忆的形成需要转录。然而，对于信息编码的精确性来说，限制相关基因程序在空间和时间上信号传递的机制仍知之甚少。我们发现，在学习过程中，早期反应基因（ERGs）的细胞表达模式受到 IIa 类组蛋白去乙酰化酶 4 和 5 的调节，这些转录抑制剂在感觉输入后会从细胞质短暂进入神经元核。在前脑中缺乏这些抑制剂的小鼠，其 ERGs 的经验依赖性表达异常广泛，突触结构和功能改变，焦虑水平升高，记忆严重受损。通过使用化学遗传技术在行为动物中急性操纵 IIa 类组蛋白去乙酰化酶的核活性，我们进一步证明，快速诱导转录程序对于记忆获取至关重要，但当形成稳定的记忆时，这些程序可能变得可有可无。这些结果为记忆存储的分子基础提供了新的见解。
