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

项目摘要 精神分裂症、躁郁症和自闭症是常见的使人衰弱的神经发育障碍， 影响了超过500万美国人。尽管经过50多年的研究，仍然没有治愈的方法， 治疗标准仍然不能令人满意。neurexin-1（NRXN 1）的杂合突变已被发现。 反复与精神分裂症（SZ）和自闭症谱系障碍（ASD）相关。的临床表现 受影响患者的NRXN 1 +/-突变（包括诊断，严重程度，预后和发病年龄） 这些突变的遗传机制仍然是未知的。此外，委员会认为， 小鼠模型不允许研究人员研究如何以及为什么一些NRXN 1 +/-缺失有更多的 对患者的有害影响。我们的目标是解决NRXN 1 +/-缺失如何干扰NRXN 1亚型 影响神经元成熟和突触功能。我们的初步数据定义了NRXN 1 在对照胎儿和成人皮质组织中的选择性剪接库，并将其与人类诱导的 来自NRXN 1 +/-病例和对照的多能干细胞（hiPSC）衍生的神经元。在此，我们建议 评价NRXN 1亚型库的实验操作在对照和NRXN 1 +/-中的作用 患者源性兴奋性和抑制性神经元。最终，我们希望直接将基因组和 在越来越精细的NRXN 1 +/-患者来源的神经元群体中的功能缺陷。

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.