Increasing attention has been drawn to the role that intracellular calcium stores play in neuronal function. Ryr3 is an intracellular calcium channel that contributes to hippocampal long-term potentiation, dendritic spine function, and higher cognitive processes. Interestingly, stimuli that increase neuronal activity upregulate the transcriptional activity of Ryr3 and augment DNA methylation in its proximal promoter. However, if these observations are valid for complex behavioral tasks such as learning and memory remains being evaluated. Relative expression analysis revealed that spatial learning increased the hippocampal levels of Ryr3, whereas mice trained using a visible platform that resulted in no spatial association showed reduced expression. Interestingly, we also observed that specific DNA modifications accompanied these opposite transcriptional changes. Increased DNA methylation was observed in hippocampal samples from spatially trained mice, and increased DNA hydroxymethylation was found in samples from mice trained using a visible platform. Both DNA modifications were not altered in control regions, suggesting that these changes are not generalized, but rather specific modifications associated with this calcium channel’s transcriptional regulation. Our two experimental groups underwent the same physical task differing only in the spatial learning component, highlighting the tight relationship between DNA modifications and transcriptional activity in a relevant context such as behavioral training. Our results complement previous observations and suggest that DNA modifications are a reliable signal for the transcriptional activity of Ryr3 and can be useful to understand how conditions such as aging and neuropathological diseases determine altered Ryr3 expression.

中文翻译：

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空间学习与 Ryanodine 受体 3 转录调控中 DNA 甲基化和 DNA 羟甲基化的拮抗剂结果相关

人们越来越关注细胞内钙储存在神经元功能中的作用。Ryr3 是一种细胞内钙通道，有助于海马长时程增强、树突棘功能和更高的认知过程。有趣的是，增加神经元活动的刺激会上调 Ryr3 的转录活性并增加其近端启动子中的 DNA 甲基化。然而，如果这些观察结果对复杂的行为任务（如学习和记忆）有效，仍有待评估。相对表达分析显示，空间学习增加了 Ryr3 的海马水平，而使用导致没有空间关联的可见平台训练的小鼠显示表达降低。有趣的是，我们还观察到特定的 DNA 修饰伴随着这些相反的转录变化。在空间训练小鼠的海马样本中观察到 DNA 甲基化增加，在使用可见平台训练的小鼠样本中发现 DNA 羟甲基化增加。两种 DNA 修饰在控制区域都没有改变，这表明这些变化不是普遍的，而是与这种钙通道的转录调控相关的特定修饰。我们的两个实验组接受了相同的体力任务，不同之处仅在于空间学习部分，突出了 DNA 修饰与转录活动在相关背景下（如行为训练）之间的紧密关系。Ryr3可用于了解衰老和神经病理学疾病等条件如何确定改变的Ryr3表达。