Department of Pediatrics/Rady Children's Hospital, Department of Cellular & Molecular Medicine, University of California San Diego, School of Medicine, La Jolla, CA, 92037, USA.
Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA, 92093, USA.
Mol Psychiatry. 2023 Apr;28(4):1571-1584. doi: 10.1038/s41380-022-01862-7. Epub 2022 Nov 16.
Prenatal alcohol exposure is the foremost preventable etiology of intellectual disability and leads to a collection of diagnoses known as Fetal Alcohol Spectrum Disorders (FASD). Alcohol (EtOH) impacts diverse neural cell types and activity, but the precise functional pathophysiological effects on the human fetal cerebral cortex are unclear. Here, we used human cortical organoids to study the effects of EtOH on neurogenesis and validated our findings in primary human fetal neurons. EtOH exposure produced temporally dependent cellular effects on proliferation, cell cycle, and apoptosis. In addition, we identified EtOH-induced alterations in post-translational histone modifications and chromatin accessibility, leading to impairment of cAMP and calcium signaling, glutamatergic synaptic development, and astrocytic function. Proteomic spatial profiling of cortical organoids showed region-specific, EtOH-induced alterations linked to changes in cytoskeleton, gliogenesis, and impaired synaptogenesis. Finally, multi-electrode array electrophysiology recordings confirmed the deleterious impact of EtOH on neural network formation and activity in cortical organoids, which was validated in primary human fetal tissues. Our findings demonstrate progress in defining the human molecular and cellular phenotypic signatures of prenatal alcohol exposure on functional neurodevelopment, increasing our knowledge for potential therapeutic interventions targeting FASD symptoms.
产前酒精暴露是导致智力障碍的首要可预防病因，并导致一系列被称为胎儿酒精谱系障碍（FASD）的诊断。酒精（EtOH）会影响多种神经细胞类型和活动，但确切的功能性病理生理效应尚不清楚。在这里，我们使用人类皮质类器官来研究 EtOH 对神经发生的影响，并在原代人类胎儿神经元中验证了我们的发现。EtOH 暴露对增殖、细胞周期和细胞凋亡产生了时间依赖性的细胞效应。此外，我们还发现 EtOH 诱导了翻译后组蛋白修饰和染色质可及性的改变，导致 cAMP 和钙信号、谷氨酸能突触发育和星形胶质细胞功能受损。皮质类器官的蛋白质组学空间分析显示，与细胞骨架、神经胶质发生和突触发生受损相关的 EtOH 诱导的特定区域改变。最后，多电极阵列电生理学记录证实了 EtOH 对皮质类器官中神经网络形成和活动的有害影响，这在原代人类胎儿组织中得到了验证。我们的研究结果表明，在功能神经发育方面，定义产前酒精暴露对人类分子和细胞表型特征的研究取得了进展，这增加了我们对针对 FASD 症状的潜在治疗干预措施的认识。
