Vaccinia-related kinases (VRKs) are multifaceted serine/threonine kinases that play essential roles in various aspects of cell signaling, cell cycle progression, apoptosis, and neuronal development and differentiation. However, the neuronal function of VRK3 is still unknown despite its etiological potential in human autism spectrum disorder (ASD). Here, we report that VRK3-deficient mice exhibit typical symptoms of autism-like behavior, including hyperactivity, stereotyped behaviors, reduced social interaction, and impaired context-dependent spatial memory. A significant decrease in dendritic spine number and arborization were identified in the hippocampus CA1 of VRK3-deficient mice. These mice also exhibited a reduced rectification of AMPA receptor–mediated current and changes in expression of synaptic and signaling proteins, including tyrosine receptor kinase B (TrkB), Arc, and CaMKIIα. Notably, TrkB stimulation with 7,8-dihydroxyflavone reversed the altered synaptic structure and function and successfully restored autism-like behavior in VRK3-deficient mice. These results reveal that VRK3 plays a critical role in neurodevelopmental disorders and suggest a potential therapeutic strategy for ASD.

牛痘相关激酶（VRK）是多方面的丝氨酸/苏氨酸激酶，在细胞信号传导，细胞周期进程，细胞凋亡以及神经元发育和分化的各个方面都发挥着重要作用。然而，尽管VRK3的神经元功能在人类自闭症谱系障碍（ASD）中具有病因学潜能，但仍是未知的。在这里，我们报告说，缺乏VRK3的小鼠表现出自闭症样行为的典型症状，包括活动过度，刻板行为，社交互动减少和上下文相关的空间记忆受损。在VRK3的海马CA1中发现树突棘数量和乔木明显减少缺陷的小鼠。这些小鼠还显示出AMPA受体介导的电流的整流降低，以及包括酪氨酸受体激酶B（TrkB），Arc和CaMKIIα在内的突触和信号蛋白表达的变化。明显地，用7，8-二羟基黄酮的TrkB刺激逆转了改变的突触结构和功能，并成功地恢复了在缺乏VRK3的小鼠中的自闭症样行为。这些结果表明，VRK3在神经发育障碍中起关键作用，并提示了ASD的潜在治疗策略。