Autism spectrum disorder (ASD) is a common and pervasive neurodevelopmental disorder, characterized by sexually divergent social deficits. Its etiology is multifactorial with an important contribution of genetic factors. Neurobeachin (Nbea), a brain-enriched multidomain scaffolding protein, is an ASD candidate gene that was found to be translocated or deleted in ASD patients. Nbea haploinsufficient (^+/−) mice have been proposed as an ASD mouse model, but its broad-spectrum social phenotype, sexual divergence and age-related robustness remain unstudied. This study compared one-year-old male and female Nbea^+/− mice and their control littermates in an extensive behavioral battery that focused on social behaviors and communication. Nbea haploinsufficiency was associated with selective, sex-dependent, quantitative and qualitative changes, including alterations in social interest and approach, ultrasonic vocalization (USV) between same-sex adult conspecifics, and preferred types of social interaction. Notably, Nbea^+/− females (but not males) displayed a significantly higher number of calls, and the mean principal frequency of their calls was higher than those of normal female littermates. Our results demonstrate that Nbea haploinsufficiency alters various aspects of social performance that are also altered in clinical ASD. The phenotype was often different between male and female mice, even though this sexual divergence was sometimes counterintuitive to observations in people with ASD, and probably influenced by differences in social interaction between male and female mice. By and large, however, this study demonstrates the clinical validity and robustness of the ASD-like phenotype of Nbea^+/− mice.

自闭症谱系障碍 (ASD) 是一种常见且普遍存在的神经发育障碍，其特征是性差异社会缺陷。其病因是多因素的，其中遗传因素有重要贡献。Neurobeachin ( Nbea ) 是一种富含大脑的多结构域支架蛋白，是一种 ASD 候选基因，在 ASD 患者中被发现易位或缺失。Nbea 单倍体不足 ( ^+/- ) 小鼠已被提议作为 ASD 小鼠模型，但其广谱社会表型、性别差异和与年龄相关的稳健性仍未得到研究。这项研究比较了一岁的男性和女性Nbea ^+/-小鼠和它们的对照同窝仔猪处于广泛的行为电池组中，专注于社交行为和交流。Nbea 单倍体不足与选择性的、性别相关的、数量和质量变化有关，包括社会兴趣和方法的改变、同性成人同种之间的超声波发声 (USV) 以及首选的社会互动类型。值得注意的是，Nbea ^+/-雌性（但不是雄性）显示出明显更多的呼叫次数，并且其呼叫的平均主要频率高于正常雌性同窝仔。我们的结果表明Nbea单倍剂量不足会改变社会表现的各个方面，而临床 ASD 也会改变这些方面。雄性和雌性小鼠的表型通常不同，尽管这种性别差异有时与 ASD 患者的观察结果相反，并且可能受到雄性和雌性小鼠之间社交互动差异的影响。然而，总的来说，这项研究证明了Nbea ^+/-小鼠的 ASD 样表型的临床有效性和稳健性。