Université Paris-Saclay, CNRS, Institut des Neurosciences Paris Saclay, 91190, Gif-sur-Yvette, France.
Université Paris-Saclay, UVSQ, Inserm, END-ICAP, 78000 Versailles, France.
Dis Model Mech. 2021 Sep 1;14(9). doi: 10.1242/dmm.049028. Epub 2021 Sep 21.
The exon-52-deleted mdx52 mouse is a critical model of Duchenne muscular dystrophy (DMD), as it features a deletion in a hotspot region of the DMD gene, frequently mutated in patients. Deletion of exon 52 impedes expression of several brain dystrophins (Dp427, Dp260 and Dp140), thus providing a key model for studying the cognitive impairment associated with DMD and testing rescuing strategies. Here, using in vivo magnetic resonance imaging and neurohistology, we found no gross brain abnormalities in mdx52 mice, suggesting that the neural dysfunctions in this model are likely at the level of brain cellular functionalities. Then, we investigated emotional behavior and fear learning performance of mdx52 mice compared to mdx mice that only lack Dp427 to focus on behavioral phenotypes that could be used in future comparative preclinical studies. mdx52 mice displayed enhanced anxiety and a severe impairment in learning an amygdala-dependent Pavlovian association. These replicable behavioral outcome measures are reminiscent of the internalizing problems reported in a quarter of DMD patients, and will be useful for preclinical estimation of the efficacy of treatments targeting brain dysfunctions in DMD.
exon-52 缺失型 mdx52 小鼠是杜氏肌营养不良症（DMD）的重要模型，因为它在 DMD 基因的热点区域缺失，该区域在患者中经常发生突变。exon-52 的缺失会阻碍几种脑肌营养不良蛋白（Dp427、Dp260 和 Dp140）的表达，因此为研究与 DMD 相关的认知障碍和测试挽救策略提供了关键模型。在这里，我们使用体内磁共振成像和神经组织学发现 mdx52 小鼠的大脑没有明显异常，这表明该模型中的神经功能障碍可能处于大脑细胞功能水平。然后，我们研究了 mdx52 小鼠与仅缺乏 Dp427 的 mdx 小鼠的情绪行为和恐惧学习表现，以关注可用于未来比较性临床前研究的行为表型。mdx52 小鼠表现出焦虑增强和在学习杏仁核依赖性条件反射关联方面严重受损。这些可复制的行为结果测量类似于四分之一 DMD 患者报告的内化问题，并且对于临床前估计针对 DMD 大脑功能障碍的治疗效果将是有用的。
