Long-term memory formation is supported by functional and structural changes of neuronal networks, which rely on de novo gene transcription and protein synthesis. The modulation of the neuronal transcriptome in response to learning depends on transcriptional and post-transcriptional mechanisms. DNA methylation writers and readers regulate the activity-dependent genomic program required for memory consolidation. The most abundant DNA methylation reader, the Methyl CpG binding domain protein 2 (MeCP2), has been shown to regulate alternative splicing, but whether it establishes splicing events important for memory consolidation has not been investigated. In this study, we identified the alternative splicing profile of the mouse hippocampus in basal conditions and after a spatial learning experience, and investigated the requirement of MeCP2 for these processes. We observed that spatial learning triggers a wide-range of alternative splicing events in transcripts associated with structural and functional remodeling and that virus-mediated knockdown of MeCP2 impairs learning-dependent post-transcriptional responses of mature hippocampal neurons. Furthermore, we found that MeCP2 preferentially affected the splicing modalities intron retention and exon skipping and guided the alternative splicing of distinct set of genes in baseline conditions and after learning. Lastly, comparative analysis of the MeCP2-regulated transcriptome with the alternatively spliced mRNA pool, revealed that MeCP2 disruption alters the relative abundance of alternatively spliced isoforms without affecting the overall mRNA levels. Taken together, our findings reveal that adult hippocampal MeCP2 is required to finetune alternative splicing events in basal conditions, as well as in response to spatial learning. This study provides new insight into how MeCP2 regulates brain function, particularly cognitive abilities, and sheds light onto the pathophysiological mechanisms of Rett syndrome, that is characterized by intellectual disability and caused by mutations in the Mecp2 gene.

中文翻译：

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MeCP2 控制小鼠海马体中空间学习诱导的选择性剪接事件

神经元网络的功能和结构变化支持长期记忆的形成，神经元网络依赖于从头基因转录和蛋白质合成。响应学习的神经元转录组的调节取决于转录和转录后机制。DNA 甲基化写入器和读取器调节记忆巩固所需的依赖于活动的基因组程序。最丰富的 DNA 甲基化阅读器，甲基 CpG 结合域蛋白 2 (MeCP2)，已被证明可以调节选择性剪接，但它是否建立了对记忆巩固很重要的剪接事件尚未得到研究。在这项研究中，我们确定了小鼠海马体在基础条件下和空间学习经验后的可变剪接谱，并调查了这些过程对 MeCP2 的要求。我们观察到空间学习在与结构和功能重塑相关的转录本中触发了广泛的选择性剪接事件，并且病毒介导的 MeCP2 敲低会损害成熟海马神经元的学习依赖性转录后反应。此外，我们发现 MeCP2 优先影响剪接方式内含子保留和外显子跳跃，并引导不同基因组在基线条件下和学习后的选择性剪接。最后，MeCP2 调节转录组与可变剪接 mRNA 库的比较分析表明，MeCP2 破坏改变了可变剪接同种型的相对丰度，而不影响整体 mRNA 水平。综合起来，我们的研究结果表明，成年海马 MeCP2 需要微调基础条件下的可变剪接事件，以及响应空间学习。这项研究为 MeCP2 如何调节大脑功能，特别是认知能力提供了新的见解，并揭示了 Rett 综合征的病理生理机制，其特征是智力障碍，由 Mecp2 基因突变引起。