BACKGROUND Autism spectrum disorder (ASD) is a neurodevelopmental disorder with unclear etiology and imprecise genetic causes. The main goal of this work was to investigate neuronal connectivity and the interplay between neurons and astrocytes from individuals with nonsyndromic ASD using induced pluripotent stem cells. METHODS Induced pluripotent stem cells were derived from a clinically well-characterized cohort of three individuals with nonsyndromic ASD sharing common behaviors and three control subjects, two clones each. We generated mixed neural cultures analyzing synaptogenesis and neuronal activity using a multielectrode array platform. Furthermore, using an enriched astrocyte population, we investigated their role in neuronal maintenance. RESULTS ASD-derived neurons had a significant decrease in synaptic gene expression and protein levels, glutamate neurotransmitter release, and, consequently, reduced spontaneous firing rate. Based on co-culture experiments, we observed that ASD-derived astrocytes interfered with proper neuronal development. In contrast, control-derived astrocytes rescued the morphological neuronal phenotype and synaptogenesis defects from ASD neuronal co-cultures. Furthermore, after identifying interleukin-6 secretion from astrocytes in individuals with ASD as a possible culprit for neural defects, we were able to increase synaptogenesis by blocking interleukin-6 levels. CONCLUSIONS Our findings reveal the contribution of astrocytes to neuronal phenotype and confirm previous studies linking interleukin-6 and autism, suggesting potential novel therapeutic pathways for a subtype of individuals with ASD. This is the first report demonstrating that glial dysfunctions could contribute to nonsyndromic autism pathophysiology using induced pluripotent stem cells modeling disease technology.

中文翻译：

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使用人类诱导的多能干细胞模拟自闭症中神经元和星形胶质细胞之间的相互作用

背景自闭症谱系障碍（ASD）是一种神经发育障碍，病因不明，遗传原因不明确。这项工作的主要目标是使用诱导多能干细胞研究非综合征 ASD 患者的神经元连接以及神经元和星形胶质细胞之间的相互作用。方法 诱导多能干细胞来自临床特征明确的队列，该队列由三个具有共同行为的非综合征 ASD 个体和三个对照受试者组成，每个受试者有两个克隆。我们使用多电极阵列平台生成了分析突触发生和神经元活动的混合神经培养物。此外，我们使用丰富的星形胶质细胞群，研究了它们在神经元维持中的作用。结果 ASD 衍生的神经元突触基因表达和蛋白质水平显着降低，谷氨酸神经递质释放，从而降低自发放电率。基于共培养实验，我们观察到 ASD 衍生的星形胶质细胞干扰了正常的神经元发育。相比之下，对照衍生的星形胶质细胞从 ASD 神经元共培养物中挽救了形态学神经元表型和突触发生缺陷。此外，在确定 ASD 个体星形胶质细胞分泌的白细胞介素 6 可能是神经缺陷的罪魁祸首后，我们能够通过阻断白细胞介素 6 水平来增加突触发生。结论我们的研究结果揭示了星形胶质细胞对神经元表型的贡献，并证实了之前将白细胞介素 6 与自闭症联系起来的研究，为 ASD 个体亚型提出了潜在的新治疗途径。