Nina Doorn, Eva J H F Voogd, Marloes R Levers, Michel J A M van Putten, Monica Frega
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引用次数: 0
Abstract
Fragmented network bursts (NBs) are observed as a phenotypic driver in many patient-derived neuronal networks on multi-electrode arrays (MEAs), but the pathophysiological mechanisms underlying this phenomenon are unknown. Here, we used our previously developed biophysically detailed in silico model to investigate these mechanisms. Fragmentation of NBs in our model simulations occurred only when the level of short-term synaptic depression (STD) was enhanced, suggesting that STD is a key player. Experimental validation with Dynasore, an STD enhancer, induced fragmented NBs in healthy neuronal networks in vitro. Additionally, we showed that strong asynchronous neurotransmitter release, NMDA currents, or short-term facilitation (STF) can support the emergence of multiple fragments in NBs by producing excitation that persists after high-frequency firing stops. Our results provide important insights into disease mechanisms and potential pharmaceutical targets for neurological disorders modeled using human induced pluripotent stem cell (hiPSC)-derived neurons.
在多电极阵列(MEA)上观察到,在许多源自患者的神经元网络中,网络爆发碎片(NBs)是一种表型驱动因素,但这种现象背后的病理生理学机制尚不清楚。在此,我们利用之前开发的生物物理详细硅学模型来研究这些机制。在我们的模型模拟中,只有当短期突触抑制(STD)水平增强时才会发生 NB 分裂,这表明 STD 是一个关键因素。在体外健康神经元网络中,使用 STD 增强剂 Dynasore 进行的实验验证诱发了 NB 分裂。此外,我们还发现,强烈的异步神经递质释放、NMDA 电流或短期促进(STF)可以在高频发射停止后产生持续的兴奋,从而支持 NB 中多个片段的出现。我们的研究结果为利用人类诱导多能干细胞(hiPSC)衍生神经元模拟神经系统疾病的发病机制和潜在药物靶点提供了重要见解。
期刊介绍:
Stem Cell Reports publishes high-quality, peer-reviewed research presenting conceptual or practical advances across the breadth of stem cell research and its applications to medicine. Our particular focus on shorter, single-point articles, timely publication, strong editorial decision-making and scientific input by leaders in the field and a "scoop protection" mechanism are reasons to submit your best papers.