Mbnl2 loss alters novel context processing and impairs object recognition memory

Myotonic dystrophy type I (DM1) patients demonstrate visuospatial dysfunction and impaired performance in tasks requiring recognition or memory of figures and objects. In DM1, CUG expansion RNAs inactivate the Muscleblind-like (MBNL) proteins. We show that constitutive Mbnl2 inactivation in DeltaE2/DeltaE2 mice, selectively impairs object recognition memory in the novel object recognition test. When exploring the context of a novel arena in which the objects are later encountered, the DeltaE2/DeltaE2 dorsal hippocampus responds with a lack of enrichment for learning and memory related pathways, mounting instead transcriptome alterations predicted to impair growth and neuron viability. In DeltaE2/DeltaE2 mice, saturation effects may prevent deployment of a functionally relevant transcriptome response during novel context exploration. Post-novel context exploration alterations in genes implicated in tauopathy and dementia are observed in the DeltaE2/DeltaE2 dorsal hippocampus. Thus MBNL2 inactivation in DM1 patients may alter novel context processing in the dorsal hippocampus and impair object recognition memory. Comparative gene expression profiling analysis of RNA-seq data for the dorsal hippocampus in 129sv/C57BL/6j Mbnl2 WT and KO mice1型强直性肌营养不良（Myotonic dystrophy type I, DM1）患者表现出视觉空间功能障碍，且在涉及图形与物体识别或记忆的任务中存在作业损伤。在DM1病理进程中，CUG扩增RNA会使肌盲样蛋白（Muscleblind-like, MBNL）失活。本研究发现，DeltaE2/DeltaE2小鼠体内的组成型Mbnl2失活，会在新物体识别实验（novel object recognition test）中选择性损伤物体识别记忆。当小鼠探索后续将放置物体的新颖环境时，DeltaE2/DeltaE2小鼠的背侧海马体（dorsal hippocampus）未出现学习记忆相关通路的富集应答，反而呈现出被预测会损害生长与神经元存活的转录组（transcriptome）改变。在DeltaE2/DeltaE2小鼠中，饱和效应可能会阻碍其在新颖环境探索过程中启动具有功能相关性的转录组应答。此外，在DeltaE2/DeltaE2小鼠的背侧海马体中，可观察到与tau蛋白病（tauopathy）及痴呆相关的基因在新颖环境探索后出现表达异常。综上，DM1患者体内的MBNL2失活可能会改变背侧海马体的新颖环境信息处理过程，并损伤物体识别记忆。本研究针对129sv/C57BL/6j背景下Mbnl2野生型（Wild Type, WT）与敲除型（Knock Out, KO）小鼠的背侧海马体RNA测序（RNA-seq）数据开展了比较基因表达谱分析。