Cell-type-specific NRXN1alpha alternative splicing changes in psychiatric disease

项目总结 精神分裂症、双相情感障碍和自闭症是常见的、使人衰弱的神经发育障碍 加在一起，影响了500多万美国人。尽管进行了50多年的研究，但目前还没有治愈方法，而且 治疗标准仍然不能令人满意。Neuresin-1(NRXN1)的杂合突变已被 反复与精神分裂症(SZ)和自闭症谱系障碍(ASD)有关。临床表现 受影响患者的NRXN1+/-突变(包括诊断、严重程度、预后和发病年龄)为 这些突变是多种多样的，影响这些突变外显的遗传机制尚不清楚。此外， 小鼠模型不允许研究人员研究一些NRXN1+/-缺失如何以及为什么会有更多 对病人的有害影响。我们的目标是解决NRXN1+/-缺失如何干扰NRXN1亚型 曲目和影响神经元成熟和突触功能。我们的初步数据定义了NRXN1 控制胎儿和成人皮质组织的选择性剪接谱系，并与人类诱导的 来自NRXN1+/-病例和对照的多能干细胞(HiPSC)来源的神经元。在此，我们建议 评估对照和NRXN1+/-中NRXN1亚型谱系的实验操作效果 病人来源的兴奋性和抑制性神经元。最终，我们希望将基因组和 日益精炼的NRXN1+/-患者来源神经元群体的功能缺陷。

PROJECT SUMMARY Schizophrenia, bipolar disorder and autism are common and debilitating neurodevelopmental disorders that together affect more than 5 million Americans. Despite more than fifty years of research, no cures exist and the standard of treatment remains unsatisfactory. Heterozygous mutations of neurexin-1 (NRXN1) have been repeatedly associated with schizophrenia (SZ) and autism spectrum disorder (ASD). The clinical presentations of NRXN1+/- mutations (including diagnosis, severity, prognosis and age-of-onset) in affected patients are diverse and the genetic mechanism affecting the penetrance of these mutations remains unknown. Moreover, mouse models do not permit researchers to study how and why some NRXN1+/- deletions have more deleterious effects in patients. Our objective is to resolve how NRXN1+/- deletions perturb the NRXN1 isoform repertoire and impact neuronal maturation and synaptic function. Our preliminary data defined the NRXN1 alternative splice repertoire in control fetal and adult cortical tissue, and compared this to human induced pluripotent stem cell (hiPSC)-derived neurons from NRXN1+/- cases and controls. Here, we propose to evaluate the effect of experimental manipulation of the NRXN1 isoform repertoire in both control and NRXN1+/- patient-derived excitatory and inhibitory neurons. Ultimately, we hope to directly correlate genomic and functional deficits across increasingly refined populations of NRXN1+/- patient-derived neurons.