NRG1-ErbB4-EAAC1信号通路在精神分裂症神经元兴奋-抑制平衡中的机制研究

Schizophrenia (SCZ) is one of the most severe neuropsychiatric disorders, which is affected by heterogeneous factors. The etiological and pathophysiological basis of SCZ are still poorly understood. A large genome wide association study (GWAS) of SCZ has convincingly identified thus far 108 risk loci with genome-wide significance, opening the way to deeper understanding of SCZ pathogenic mechanisms. However, deciphering how these risk loci affect gene expression resulting in SCZ pathogenesis is not a trivial task. One caveat in current expression quantitative trait loci (eQTL) studies is that most of the attempts to connect gene expression levels with risk loci are based on transcriptome studies carried out on postmortem tissues, which typically involve subjects with chronic illness and years of exposure to psychotropic medications. Such studies cannot address pathogenic mechanisms operational during development. Thus, disease-specific developmental brain tissue will be needed to unravel the role of these risk genes during the critical developmental periods. Induced pluripotent stem cell (iPSC) technology allow us to generate such patient-specific developmental brain tissues with the same genetic make-up as the patient brains. .In this study, we will use homogeneous populations of cortical interneurons (cINs) derived from iPSCs to analyze cIN-intrinsic deficits in SCZ. Furthermore, we’ll find out how the NRG1-ErbB4-EAAC1 pathway affects the excitatory-inhibition balance in PV-Cre;ErbB4-/- schizophrenia mice model the inhibitory-organiod (IO) and excitatory-organoid (EO) model. This study will illuminate the mechanistic basis of SCZ pathogenesis and to identify potential novel therapeutic targets.

精神分裂症是临床常见的重性精神疾病之一，是一种受多重异质性病因影响的复杂性疾病。尽管多中心大样本量的全基因组关联分析（GWAS）和表达数量性状位点（eQTL）的研究为精神分裂症的研究起到了非常重要的指导作用，但是这些研究成果距离最终阐明精神分裂症发病机制及提出可行的治疗措施还有很长的临床转化过程。本研究将针对这一亟待解决的关键问题，通过建立精神分裂症“临床样本-动物模型-类脑模型”的转化研究模式，分别在诱导多能干细胞iPSC定向分化的中间神经元、PV-Cre;ErbB4-/-精神分裂症模型小鼠和从iPSC样本制备的兴奋性-抑制性神经元共培养的类脑模型中，探索对精神分裂症发病机制具有重要影响的NRG1-ErbB4-EAAC1信号通路在神经元兴奋-抑制平衡中的作用机制。通过本项目的研究，以期为精神分裂症发病机制的研究提供新的思路，进而为探寻精神分裂症潜在的治疗方法奠定理论基础。

精神分裂症是临床常见的重性精神疾病之一，是一种受多重异质性病因影响的复杂性疾病。尽管多中心大样本量的全基因组关联分析（GWAS）和表达数量性状位点（eQTL）的研究为精神分裂症的研究起到了非常重要的指导作用，但是这些研究成果距离最终阐明精神分裂症发病机制及提出可行的治疗措施还有很长的临床转化过程。本研究将针对这一亟待解决的关键问题，通过建立精神分裂症“临床样本-动物模型-类脑模型”的转化研究模式，分别在诱导多能干细胞iPSC定向分化的中间神经元、PV-ErbB4-/-精神分裂症模型小鼠和从iPSC样本制备的兴奋性-抑制性神经元共培养的类脑模型中，探索对精神分裂症发病机制具有重要影响的NRG1-ErbB4-EAAC1信号通路在神经元兴奋-抑制平衡中的作用机制。通过本项目的研究，以期为精神分裂症发病机制的研究提供新的思路，进而为探寻精神分裂症潜在的治疗方法奠定理论基础。