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 characterized gait using the DigiGait assay in two different murine NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1+/R681X mouse, which models a NF1 patient-derived heterozygous germline NF1 mutation. Longitudinal data were collected across four developmental time points (postnatal days 21–30) and one early adulthood time point. Compared to wildtype 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 development in the Nf1+/R681X mice persisted into early adulthood, including increased stride length and decreased stride frequency, while developmental abnormalities in the CD model largely resolved by adulthood. These findings suggest that the subcomponents of gait 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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两种神经发育障碍小鼠模型的共同发育步态中断

诸如异常步态等运动缺陷是许多神经发育障碍 (NDD) 的一种未被充分认识但具有特征的表型，包括威廉姆斯综合征 (WS) 和 1 型神经纤维瘤病 (NF1)。与认知表型相比，步态表型在人类和模型生物中都可以轻松且可比较地评估，并由明确定义的中枢神经系统电路控制。在 NDDs 之间发现共同的步态表型可能表明共同的细胞和分子缺陷，并突出简单的结果变量，以潜在地量化 NDDs 的纵向治疗效果。我们在两种不同的小鼠 NDD 模型中使用 DigiGait 测定来表征步态：完全缺失 (CD) 小鼠，它模拟完整 WS 基因座的半合子丢失，以及 Nf1+/R681X 小鼠，它模拟 NF1 患者衍生的杂合种系 NF1 突变. 在四个发育时间点（出生后 21-30 天）和一个成年早期时间点收集纵向数据。与野生型同窝对照相比，两种模型在发育过程中都表现出明显相似的空间、时间和姿势步态异常。发育中的 CD 小鼠也显示出变异性指标的显着下降。Nf1+/R681X 小鼠在整个发育过程中观察到的多种步态异常一直持续到成年早期，包括步幅增加和步频降低，而 CD 模型中的发育异常在成年期很大程度上得到解决。这些发现表明，受 NDD 影响的步态子成分显示出疾病之间的重叠以及一些疾病特异性特征，这些特征可能会随着发展过程而改变。我们将空间、时间、