De novo mutations and copy number deletions in NRXN1 (2p16.3) pose a significant risk for schizophrenia (SCZ). It is unclear how NRXN1 deletions impact cortical development in a cell type-specific manner and disease background modulates these phenotypes. Here, we leveraged human pluripotent stem cell-derived forebrain organoid models carrying NRXN1 heterozygous deletions in isogenic and SCZ patient genetic backgrounds and conducted single-cell transcriptomic analysis over the course of brain organoid development from 3 weeks to 3.5 months. Intriguingly, while both deletions similarly impacted molecular pathways associated with ubiquitin-proteasome system, alternative splicing, and synaptic signaling in maturing glutamatergic and GABAergic neurons, SCZ-NRXN1 deletions specifically perturbed developmental trajectories of early neural progenitors and accumulated disease-specific transcriptomic signatures. Using calcium imaging, we found that both deletions led to long-lasting changes in spontaneous and synchronous neuronal networks, implicating synaptic dysfunction. Our study reveals developmental-timing- and cell-type-dependent actions of NRXN1 deletions in unique genetic contexts.

NRXN1 (2p16.3)中的从头突变和拷贝数缺失对精神分裂症 (SCZ) 构成重大风险。目前尚不清楚NRXN1缺失如何以细胞类型特异性方式影响皮质发育，以及疾病背景如何调节这些表型。在这里，我们利用在等基因和 SCZ 患者遗传背景中携带NRXN1杂合缺失的人类多能干细胞来源的前脑类器官模型，并在 3 周至 3.5 个月的脑类器官发育过程中进行单细胞转录组分析。有趣的是，虽然这两种缺失类似地影响了成熟谷氨酸能和 GABA 能神经元中与泛素蛋白酶体系统、选择性剪接和突触信号传导相关的分子途径，但 SCZ- NRXN1缺失特别扰乱了早期神经祖细胞的发育轨迹，并积累了疾病特异性转录组特征。使用钙成像，我们发现这两种缺失都会导致自发和同步神经元网络的长期变化，暗示突触功能障碍。我们的研究揭示了NRXN1缺失在独特遗传背景下的发育时间和细胞类型依赖性作用。