神经精神疾病易感基因ANK3调节突触前分化的机制

突触发育异常是导致神经精神疾病的重要因素。神经精神疾病的病人基因组学研究提示ANK3 (ankryin-G)是高风险疾病基因，但它如何影响突触发育尚不清楚。现有的研究揭示突触后神经元的ankyrin-G可引导突触形成或调节可塑性，我们发表的工作显示低表达ankyrin-G（UNC-44L）的秀丽线虫突变体中有突触前分化的缺陷（Chen et al., Genes & Development, 2015）。当ankyrin-G过表达时，我们观察到增强的突触前分化。结合ankyrin-G低表达和高表达突变体中特异的突触前分化表型，我们拟：1）确定调控突触前分化的ankyrin-G蛋白复合物组分；2）研究蛋白复合物组分调控突触前分化的机制；3）在高等哺乳动物中探索此蛋白复合物的保守性。我们的研究可能发现ankyrin-G调控突触发育的新机制，也可能为理解神经精神疾病的发病机制提供新思路。

Synapses have been implicated as key sites of pathogenesis in many neuropsychiatric disorders. Genome-wide association studies from patients with neuropsychiatric disorders including bipolar disorder suggests that ANK3, which encodes ankyrin-G, is an important risk gene. However, the roles that ankyrin-G may play in synapses are largely unknown. Current studies indicate that ankyrin-G expressed in the postsynaptic neurons guides synaptogenesis of the inhibitory GABAergic interneuron at the axon initial segment and regulates plasticity of both GABAergic and glutamatergic synapses. Our published work found that a mutant C. elegans strain with lower ankyrin-G (UNC-44L) expression displays defective presynaptic differentiation (Chen et al., Genes & Development, 2015). Our following-up work suggested that the presynaptic differentiation is enhanced in a mutant strain with higher ankyrin-G expression. By taking advantages of both loss-of-function and gain-of-function mutant strains, we plan to identify the ankyrin-G interacting complex which specifically regulates the organization of presynaptic terminals. We will study which steps of presynaptic structural formation are controlled by this complex. We will further explore whether this complex is conserved in higher organisms. Our results may provide valuable insights in understanding of synaptogenesis in all organisms and the development of new treatments for neuropsychiatric disorders.