Gene copy number variants play an important role in the occurrence of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features. Earlier studies highlighted the implication of Kctd13 genetic imbalance in 16p11.2 deletion through the regulation of the RHOA pathway. Here, we generated a new mouse model with a small deletion of two key exons in Kctd13. Then, we targeted the RHOA pathway to rescue the cognitive phenotypes of the Kctd13 and 16p11.2 deletion mouse models in a pure genetic background. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase, for six weeks in mouse models carrying a heterozygous inactivation of Kctd13, or the deletion of the entire 16p11.2 BP4-BP5 homologous region. We found that the small Kctd13 heterozygous deletion induced a cognitive phenotype similar to the whole deletion of the 16p11.2 homologous region, in the Del/+ mice. We then showed that chronic fasudil treatment can restore object recognition memory in adult heterozygous mutant mice for Kctd13 and for 16p11.2 deletion. In addition, learning and memory improvement occurred in parallel to change in the RHOA pathway. The Kcdt13 mutant line does not recapitulate all the phenotypes found in the 16p11.2 Del/+ model. In particular, the locomotor activity was not altered at 12 and 18 weeks of age and the object location memory was not defective in 18-week old mutants. Similarly, the increase in locomotor activity was not modified by the treatment in the 16p11.2 Del/+ mouse model, suggesting that other loci were involved in such defects. Rescue was observed only after four weeks of treatment but no long-term experiment has been carried out so far. Finally, we did not check the social behaviour, which requires working in another hybrid genetic background. These findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the relevance of the RHOA pathway as a therapeutic path for 16p11.2 deletion. In addition, they reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 models in older mice.

中文翻译：

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靶向 RHOA 通路可改善成人 Kctd13 和 16p11.2 缺失小鼠模型的学习和记忆

基因拷贝数变异在神经发育障碍的发生中起重要作用。特别是，16p11.2 基因座的缺失与自闭症谱系障碍、智力障碍和其他几个特征有关。早期的研究强调了 Kctd13 遗传失衡在 16p11.2 缺失中通过调节 RHOA 途径的意义。在这里，我们生成了一个新的小鼠模型，其中删除了 Kctd13 中的两个关键外显子。然后，我们针对 RHOA 途径在纯遗传背景中拯救 Kctd13 和 16p11.2 缺失小鼠模型的认知表型。我们在携带 Kctd13 杂合失活或整个 16p11.2 缺失的小鼠模型中长期使用法舒地尔 (HA1077)（Rho 相关蛋白激酶抑制剂）六周。2 BP4-BP5 同源区。我们发现，在 Del/+ 小鼠中，小的 Kctd13 杂合缺失诱导了类似于 16p11.2 同源区域的整个缺失的认知表型。然后我们表明，慢性法舒地尔治疗可以恢复成年杂合突变小鼠的物体识别记忆，用于 Kctd13 和 16p11.2 缺失。此外，学习和记忆的改善与 RHOA 通路的变化同时发生。Kcdt13 突变系不能概括在 16p11.2 Del/+ 模型中发现的所有表型。特别是，自发活动在 12 和 18 周龄时没有改变，并且对象位置记忆在 18 周龄的突变体中没有缺陷。类似地，在 16p11.2 Del/+ 小鼠模型中的处理未改变运动活性的增加，表明其他位点与此类缺陷有关。仅在治疗 4 周后才观察到救援，但目前尚未进行长期实验。最后，我们没有检查社会行为，这需要在另一个混合遗传背景下工作。这些发现证实 KCTD13 是导致 16p11.2 缺失患者认知缺陷的一个靶基因，以及 RHOA 通路作为 16p11.2 缺失治疗途径的相关性。此外，它们加强了与老年小鼠 16p11.2 模型中发现的认知缺陷相关的其他基因的贡献。这些发现证实 KCTD13 是导致 16p11.2 缺失患者认知缺陷的一个靶基因，以及 RHOA 通路作为 16p11.2 缺失治疗途径的相关性。此外，它们加强了与老年小鼠 16p11.2 模型中发现的认知缺陷相关的其他基因的贡献。这些发现证实 KCTD13 是导致 16p11.2 缺失患者认知缺陷的一个靶基因，以及 RHOA 通路作为 16p11.2 缺失治疗途径的相关性。此外，它们加强了与老年小鼠 16p11.2 模型中发现的认知缺陷相关的其他基因的贡献。