Impact of alcohol exposure on neural development and network formation in human cortical organoids.
Impact of alcohol exposure on neural development and network formation in human cortical organoids.
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DOI：
10.1038/s41380-022-01862-7
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发表时间：
2023-04
影响因子：
11
通讯作者：
Trujillo, Cleber A.
中科院分区：
文献类型：
--
作者：
Adams, Jason W.;Negraes, Priscilla D.;Truong, Justin;Tran, Timothy;Szeto, Ryan A.;Guerra, Bruno S.;Herai, Roberto H.;Teodorof-Diedrich, Carmen;Spector, Stephen A.;Del Campo, Miguel;Jones, Kenneth L.;Muotri, Alysson R.;Trujillo, Cleber A.
产前酒精暴露是智力残疾的最重要的可预防病因，并导致一系列被称为胎儿酒精谱系障碍(FASD)的诊断。酒精(Etoh)影响多种神经细胞类型和活性，但对人胎儿大脑皮层的确切功能病理生理影响尚不清楚。在这里，我们使用人类皮质有机体来研究乙醇对神经发生的影响，并在原代人类胚胎神经元中验证了我们的发现。乙醇暴露对细胞增殖、细胞周期和细胞凋亡产生时间依赖性的影响。此外，我们发现乙醇诱导的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的损害。皮质类器官的蛋白质组空间图谱显示，乙醇诱导的区域特异性改变与细胞骨架、神经胶质发生和突触形成障碍有关。最后，多电极阵列电生理记录证实了乙醇对神经网络形成和皮质类器官活动的有害影响，这一点在原代人胎儿组织中得到了验证。我们的发现表明，在确定产前酒精暴露对功能神经发育的人类分子和细胞表型特征方面取得了进展，增加了我们对针对FASD症状的潜在治疗干预措施的知识。
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.
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影响因子：
23.9
作者：
Bershteyn M;Nowakowski TJ;Pollen AA;Di Lullo E;Nene A;Wynshaw-Boris A;Kriegstein AR
通讯作者：
Kriegstein AR
影响因子：
4.4
作者：
GUERRI, C;SAEZ, R;RENAUPIQUERAS, J
通讯作者：
RENAUPIQUERAS, J
影响因子：
14.8
作者：
Garcia, Benjamin A.;Mollah, Sahana;Hunt, Donald F.
通讯作者：
Hunt, Donald F.
影响因子：
8
作者：
Hoyme, H. Eugene;Kalberg, Wendy O.;May, Philip A.
通讯作者：
May, Philip A.
影响因子：
2.8
作者：
Anthony, Bruce;Zhou, Feng C.;Ruiz, Joseph
通讯作者：
Ruiz, Joseph