精神分裂症易感基因DGCR2在突触形成中的功能与机制

人染色体22q11.2区域缺失引起一系列发育障碍，其中约有23-43%的病人患有精神分裂症（SCZ）。基因DGCR2位于该缺失区域，本身也是SCZ易感基因，在SCZ病人脑中表达降低，但它在SCZ中的病理生理机制完全不清楚。我们的预实验发现DGCR2在海马高表达且定位在突触后致密部位；DGCR2缺陷小鼠海马区锥体神经元树突棘密度和mEPSC频率均降低，提示DGCR2可能参与兴奋性突触形成，但具体分子机制并不清楚。本项目将围绕该科学问题，从DGCR2自身包含PDZ结合结构域以及可能的细胞黏附功能入手，探索PDZ蛋白或相关细胞黏附因子是否介导DGCR2在突触形成中发挥作用，从而在分子水平研究DGCR2在突触形成中的功能与机制。更进一步结合相关行为学范式检测DGCR2缺陷小鼠是否表现出类似SCZ的行为学异常，以期阐明DGCR2在SCZ发生发展中的病理生理机制，为SCZ治疗提供新的线索和思路。

22q11.2 deletion is a common micro-deletion that causes an array of developmental defects including 22q11 deletion syndrome (22q11DS). About 23-43% of patients with 22q11DS develops schizophrenia (SCZ). SCZ susceptibility gene DGCR2 (DiGeorge Syndrome Critical Region Gene 2) is one of the 30-60 genes in the 22q11.2 deletion, and reduced expression of DGCR2 has been found in SCZ patients. In our preliminary experiments, we found that DGCR2 is expressed mainly in the hippocampus and localized to the post-synaptic densities (PSDs). Moreover, dendritic spine density and mEPSCs frequency are reduced in the hippocampal pyramidal neurons in DGCR2 deficient mice. These results suggest DGCR2 play a role in excitatory synapse formation. However, little is known about the underlying mechanisms. Considering that DGCR2 harbors a PDZ-binding motif and is a putative adhesion receptor, in this study we will explore if DGCR2 cooperates with PDZ containing proteins or synaptic adhesion molecules in the synapse formation. Moreover, we will use behavioral paradigms to detect if DGCR2 deficient mice exhibit SCZ-related abnormal behaviors. This study will be helpful for further understanding the molecular physiopathological mechanisms of DGCR2 in SCZ, and could possibly lead to strategy for the effective treatment of SCZ.