Motor deficits such as abnormal gait are an underappreciated yet characteristic phenotype of many neurodevelopmental disorders (NDDs), including Williams Syndrome (WS) and Neurofibromatosis Type 1 (NF1). Compared to cognitive phenotypes, gait phenotypes are readily and comparably assessed in both humans and model organisms, and are controlled by well-defined CNS circuits. Discovery of a common gait phenotype between NDDs might suggest shared cellular and molecular deficits and highlight simple outcome variables to potentially quantify longitudinal treatment efficacy in NDDs. We therefore characterized gait using the DigiGait assay in two different NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1^+/R681X mouse, which models a patient-derived heterozygous germline NF1 mutation. We collected longitudinal data across five developmental time points (postnatal days 21-30) and one early adulthood time point. Compared to wild type littermate controls, both models displayed markedly similar spatial, temporal, and postural gait abnormalities during development. Developing CD mice also displayed significant decreases in variability metrics. Multiple gait abnormalities observed across Nf1^+/R681X mouse development persisted into early adulthood, including increased stride length and decreased stride frequency, while developmental abnormalities in CD mice largely resolved by adulthood. These findings suggest that gait subcomponents affected in NDDs show overlap between disorders as well as some disorder-specific features, which may change over the course of development. Our incorporation of spatial, temporal, and postural gait measures also provides a template for gait characterization in other NDD models, and a platform to examining circuits or longitudinal therapeutics.

中文翻译：

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在两种神经发育障碍小鼠模型中共有的发育步态中断

诸如步态异常之类的运动功能障碍是许多神经发育障碍（NDD），包括威廉姆斯综合征（WS）和1型神经纤维瘤病（NF1）的一种未被充分认识的特征表型。与认知表型相比，步态表型在人类和模型生物中均容易且可比较地评估，并且由定义明确的CNS电路控制。在NDD之间发现一个共同的步态表型可能表明存在共同的细胞和分子缺陷，并突出了简单的结果变量以潜在地量化NDD中的纵向治疗效果。因此，我们在两种不同的NDD模型中使用DigiGait分析对步态进行了表征：完全缺失（CD）小鼠和Nf1 ^{+ / R681X}，其中完全缺失（CD）小鼠模拟了整个WS基因座的半合子丢失小鼠，它模拟了患者来源的杂合种系NF1突变。我们收集了五个发育时间点（出生后21-30天）和一个成年早期时间点的纵向数据。与野生型同窝对照相比，两个模型在发育过程中均显示出明显相似的空间，时间和姿势步态异常。发育中的CD小鼠的变异性指标也显着降低。在Nf1 ^{+ / R681X上}观察到多种步态异常小鼠的发育一直持续到成年早期，包括步幅增加和步幅降低，而CD小鼠的发育异常在成年后得到很大程度的缓解。这些发现表明，受NDD影响的步态亚组分表现出疾病之间的重叠以及某些疾病特有的特征，这些特征可能在发展过程中发生变化。我们将空间，时间和姿势步态测量结合起来，还为其他NDD模型中的步态表征提供了模板，并为检查回路或纵向疗法提供了平台。