Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. Individuals with ASTN2 mutations exhibit neurodevelopmental disorders, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), learning difficulties, and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditional Astn2 knockout (KO and cKO, respectively) mouse lines. Astn2 KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity, repetitive behaviors, altered behavior in the three-chamber test, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors are also prominent in Astn2 cKO animals, but they do not show altered behavior in the three-chamber test. By Golgi staining, Astn2 KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron–glial adhesion protein. Immunohistochemistry and electron microscopy demonstrate a significant increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents in the Astn2 KO animals, suggesting that pre- and postsynaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.

中文翻译：

---

缺乏 Astn2 的小鼠具有类似 ASD 的行为并改变小脑回路特性


Astrotactin 2 (ASTN2) 是一种在小脑中高度表达的跨膜神经元蛋白，在受体运输中发挥作用并调节小脑浦肯野细胞 (PC) 突触活性。携带 ASTN2 突变的个体表现出神经发育障碍，包括自闭症谱系障碍 (ASD)、注意力缺陷/多动障碍 (ADHD)、学习困难和语言发育迟缓。为了提供小脑在 ASD 相关行为中的作用的遗传模型并研究 ASTN2 在小脑回路功能中的作用，我们生成了全局和 PC 特异性条件 Astn2 敲除（分别为 KO 和 cKO）小鼠系。 Astn2 KO 小鼠表现出强烈的 ASD 相关行为表型，包括分离引起的幼崽超声波发声显着减少、多动、重复行为、三腔测试中的行为改变以及小脑依赖性眨眼条件反射受损。多动和重复行为在 Astn2 cKO 动物中也很突出，但它们在三腔测试中没有表现出行为改变。通过高尔基体染色，Astn2 KO PC 的树突棘密度和丝状伪足数量出现区域特异性变化。 Astn2 KO 小脑的蛋白质组学分析揭示了 ASTN2 家族成员 ASTN1（一种神经元-胶质细胞粘附蛋白）的显着上调。免疫组织化学和电子显微镜显示 Astn2 KO 动物分子层中伯格曼胶质细胞体积显着增加。电生理学实验表明，Astn2 KO 动物中自发性兴奋性突触后电流 (EPSC) 的频率降低，自发性 EPSC 和抑制性突触后电流的幅度增加，表明突触传递的前和突触后成分发生了改变。 因此，ASTN2 调节 ASD 样行为和小脑回路特性。