Gene copy number variants (CNV) have an important role in the appearance 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 the 16p11.2 deletion through the regulation of the RHOA pathway. Here, we target the pathway and rescue the cognitive phenotypes of the 16p11.2 deletion mouse models. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase (ROCK), in mouse models carrying a heterozygous inactivation of Kctd13, or the deletion of the entire 16p11.2 BP4-BP5 region. We focused our attention on the most robust cognitive phenotypes seen in the 16p11.2 models and we showed that a chronic fasudil treatment can restore object recognition memory in both mouse models but does not change other behavioural traits. These findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the pertinence of the RHOA pathway as a therapeutic path and reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 CNV models.

中文翻译：

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靶向RHOA途径可改善Kctd13和16p11.2缺失小鼠模型的学习和记忆能力。

基因拷贝数变异（CNV）在神经发育障碍的出现中具有重要作用。特别是，16p11.2基因座的缺失与自闭症谱系障碍，智力残疾和其他几个特征有关。早期的研究强调了通过调控RHOA途径在16p11.2缺失中Kctd13遗传失衡的含义。在这里，我们靶向通路并拯救16p11.2缺失小鼠模型的认知表型。我们在携带Kctd13杂合失活或缺失整个16p11.2 BP4-BP5区域的小鼠模型中使用了fasudil（HA1077）（Rho相关蛋白激酶（ROCK）的抑制剂）的长期给药。我们将注意力集中在16p11中看到的最可靠的认知表型上。在2种模型中，我们证明了慢性法舒地尔治疗可以在两种小鼠模型中恢复对象识别记忆，但不会改变其他行为特征。这些发现证实了KCTD13是导致16p11.2缺失患者认知缺陷的一种靶基因，并且RHOA途径的相关性作为治疗途径，并增强了与16p11.2 CNV中发现的认知缺陷有关的其他基因的贡献。楷模。