Objective:

Schizophrenia is a brain disorder that originates during neurodevelopment and has complex genetic and environmental etiologies. Despite decades of clinical evidence of altered striatal function in affected patients, studies examining its cellular and molecular mechanisms in humans are limited. To explore neurodevelopmental alterations in the striatum associated with schizophrenia, the authors established a method for the differentiation of induced pluripotent stem cells (iPSCs) into ventral forebrain organoids (VFOs).

Methods:

VFOs were generated from postmortem dural fibroblast–derived iPSCs of four individuals with schizophrenia and four neurotypical control individuals for whom postmortem caudate genotypes and transcriptomic data were profiled in the BrainSeq neurogenomics consortium. Individuals were selected such that the two groups had nonoverlapping schizophrenia polygenic risk scores (PRSs).

Results:

Single-cell RNA sequencing analyses of VFOs revealed differences in developmental trajectory between schizophrenia and control individuals in which inhibitory neuronal cells from the patients exhibited accelerated maturation. Furthermore, upregulated genes in inhibitory neurons in schizophrenia VFOs showed a significant overlap with upregulated genes in postmortem caudate tissue of individuals with schizophrenia compared with control individuals, including the donors of the iPSC cohort.

Conclusions:

The findings suggest that striatal neurons derived from high-PRS individuals with schizophrenia carry abnormalities that originated during early brain development and that the VFO model can recapitulate disease-relevant cell type–specific neurodevelopmental phenotypes in a dish.

中文翻译：

---

用来自同一精神分裂症患者的腹侧前脑类器官重述供体大脑的扰动纹状体基因表达动态

客观的：

精神分裂症是一种起源于神经发育过程的脑部疾病，具有复杂的遗传和环境病因。尽管数十年的临床证据表明受影响患者的纹状体功能发生了改变，但对其在人类中的细胞和分子机制的研究仍然有限。为了探索与精神分裂症相关的纹状体神经发育改变，作者建立了一种将诱导多能干细胞（iPSC）分化为腹侧前脑类器官（VFO）的方法。

方法：

VFO 是由四名精神分裂症患者和四名神经典型对照个体的死后硬脑膜成纤维细胞衍生的 iPSC 生成的，BrainSeq 神经基因组学联盟对这些个体的死后尾状核基因型和转录组数据进行了分析。选择个体时，两组的精神分裂症多基因风险评分（PRS）不重叠。

结果：

VFO 的单细胞 RNA 测序分析揭示了精神分裂症患者和对照个体之间发育轨迹的差异，其中来自患者的抑制性神经元细胞表现出加速成熟。此外，与对照组（包括 iPSC 队列的供体）相比，精神分裂症 VFO 中抑制性神经元中的上调基因与精神分裂症患者死后尾状核组织中的上调基因显着重叠。

结论：

研究结果表明，源自高 PRS 精神分裂症患者的纹状体神经元携带起源于早期大脑发育过程的异常，并且 VFO 模型可以在培养皿中重现与疾病相关的细胞类型特异性神经发育表型。