Role of the Sez6 family in synapse pruning

补体促进神经胶质细胞的突触修剪，以改善神经回路， 发育，但也可能在病理上破坏成熟的，必要的突触的背景下， 神经炎症免疫功能障碍和突触修剪的不平衡， 与自闭症谱系障碍（ASD）有关，最近的研究表明， 可以连接互补。在本申请中要检验的中心假设是， Sez6基因家族，其成员已被鉴定为ASD易感基因， 一种新的、突触定位的补体调节剂， 与ASD相关的突触修剪。在目标1中，我们将定义补充监管属性 Sez6、Sez6L和Sez6L2的抗体。我们会调查 Sez6家族是否可以在体外阻止补体在突触处沉积。在目标2中， 将使用16 p11.2缺失的自闭症小鼠模型，其中Sez6L2与其他基因一起沿着丢失。 基因，以确定增强的补体依赖性突触修剪是否发生在 视觉系统中的视网膜神经突触。Sez6L2淘汰赛也将进行测试， 验证发现并确认SezL2对16p11.2表型的重要性。在 总的来说，我们希望从这些实验中获得的数据能够促进我们的理解 Sez6蛋白在补体介导的突触机制中的作用 这可能解释了这个基因家族如何导致易感性 到ASD。

Complement promotes synaptic pruning by glia in order to refine neural circuits during development, but may also pathologically destroy mature, essential synapses in the context of neuroinflammation. Immune dysfunction and an imbalance in synaptic pruning have been implicated in autism spectrum disorder (ASD), and recent studies suggest that dysregulation of complement may be connected. The central hypothesis to be tested in this application is that the Sez6 gene family, whose members have been identified as ASD susceptibility genes, are novel, synaptically localized, complement regulators that are required to prevent aberrant synaptic pruning related to ASD. In Aim 1, we will define the complement regulatory properties of Sez6, Sez6L, and Sez6L2 using standard complement assays. We will then investigate whether the Sez6 family can prevent complement deposition at synapses in vitro. In Aim 2, we will use the 16p11.2 deletion mouse model of autism, in which Sez6L2 is lost along with other genes, to determine if enhanced complement dependent synapse pruning occurs at retinogeniculate synapses in the visual system. A Sez6L2 knockout will also be tested in order to validate findings and confirm the importance of SezL2 to the 16p11.2 phenotype. In aggregate, we expect the data obtained from these experiments to advance our understanding of the role of Sez6 proteins in mechanisms underlying complement-mediated synapse elimination during development that may explain how this gene family contributes susceptibility to ASD.