Deepening the role of excitation/inhibition balance in human iPSCs-derived neuronal networks coupled to MEAs during long-term development.

IF 3.7 3区 医学 Q2 ENGINEERING, BIOMEDICAL Journal of neural engineering Pub Date : 2023-09-19 DOI:10.1088/1741-2552/acf78b
Giulia Parodi, Martina Brofiga, Vito Paolo Pastore, Michela Chiappalone, Sergio Martinoia
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Abstract

Objective.The purpose of this study is to investigate whether and how the balance between excitation and inhibition ('E/I balance') influences the spontaneous development of human-derived neuronal networksin vitro. To achieve that goal, we performed a long-term (98 d) characterization of both homogeneous (only excitatory or inhibitory neurons) and heterogeneous (mixed neuronal types) cultures with controlled E/I ratios (i.e. E:I 0:100, 25:75, 50:50, 75:25, 100:0) by recording their electrophysiological activity using micro-electrode arrays.Approach.Excitatory and inhibitory neurons were derived from human induced pluripotent stem cells (hiPSCs). We realized five different configurations by systematically varying the glutamatergic and GABAergic percentages.Main results.We successfully built both homogeneous and heterogeneous neuronal cultures from hiPSCs finely controlling the E/I ratios; we were able to maintain them for up to 3 months. Homogeneity differentially impacted purely inhibitory (no bursts) and purely excitatory (few bursts) networks, deviating from the typical traits of heterogeneous cultures (burst dominated). Increased inhibition in heterogeneous cultures strongly affected the duration and organization of bursting and network bursting activity. Spike-based functional connectivity and image-based deep learning analysis further confirmed all the above.Significance.Healthy neuronal activity is controlled by a well-defined E/I balance whose alteration could lead to the onset of neurodevelopmental disorders like schizophrenia or epilepsy. Most of the commonly usedin vitromodels are animal-derived or too simplified and thus far from thein vivohuman condition. In this work, by performing a long-term study of hiPSCs-derived neuronal networks obtained from healthy human subjects, we demonstrated the feasibility of a robustin vitromodel which can be further exploited for investigating pathological conditions where the E/I balance is impaired.

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在长期发展过程中,加深人类iPSC衍生的神经元网络与MEA耦合的兴奋/抑制平衡的作用。
客观的本研究的目的是研究兴奋和抑制之间的平衡(“E/I平衡”)是否以及如何影响体外人源性神经元网络的自发发展。为了实现这一目标,我们对具有受控E/I比(即E:I 0:100、25:75、50:50、75:25、100:0)的同质(仅兴奋性或抑制性神经元)和异质(混合神经元类型)培养物进行了长期(98天)表征,方法是使用微电极阵列记录其电生理活性。方法兴奋性和抑制性神经元来源于人类诱导多能干细胞。通过系统地改变谷氨酸能和GABA能的百分比,我们实现了五种不同的构型。主要结果。我们成功地从精细控制E/I比率的hiPSC构建了同质和异质神经元培养物;我们能够维护它们长达3个月。同质性对纯抑制性(无爆发)和纯兴奋性(很少爆发)网络产生了不同的影响,偏离了异质文化的典型特征(爆发主导)。异质培养中抑制作用的增加强烈影响爆发和网络爆发活动的持续时间和组织。基于Spike的功能连接和基于图像的深度学习分析进一步证实了上述一切。意义健康的神经元活动由明确的E/I平衡控制,其改变可能导致精神分裂症或癫痫等神经发育障碍的发作。大多数常用的玻璃体模型都是动物来源的,或者过于简化,因此与活体人类条件相去甚远。在这项工作中,通过对从健康人类受试者获得的hiPSCs衍生的神经元网络进行长期研究,我们证明了robustin玻璃体模型的可行性,该模型可进一步用于研究E/I平衡受损的病理条件。
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来源期刊
Journal of neural engineering
Journal of neural engineering 工程技术-工程:生物医学
CiteScore
7.80
自引率
12.50%
发文量
319
审稿时长
4.2 months
期刊介绍: The goal of Journal of Neural Engineering (JNE) is to act as a forum for the interdisciplinary field of neural engineering where neuroscientists, neurobiologists and engineers can publish their work in one periodical that bridges the gap between neuroscience and engineering. The journal publishes articles in the field of neural engineering at the molecular, cellular and systems levels. The scope of the journal encompasses experimental, computational, theoretical, clinical and applied aspects of: Innovative neurotechnology; Brain-machine (computer) interface; Neural interfacing; Bioelectronic medicines; Neuromodulation; Neural prostheses; Neural control; Neuro-rehabilitation; Neurorobotics; Optical neural engineering; Neural circuits: artificial & biological; Neuromorphic engineering; Neural tissue regeneration; Neural signal processing; Theoretical and computational neuroscience; Systems neuroscience; Translational neuroscience; Neuroimaging.
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