Department of Biological Sciences, Columbia University, New York, NY, USA.
Mortimer B. Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY, USA.
Nat Commun. 2022 Jun 9;13(1):3340. doi: 10.1038/s41467-022-31073-1.
Advances in 3D neuronal cultures, such as brain spheroids and organoids, are allowing unprecedented in vitro access to some of the molecular, cellular and developmental mechanisms underlying brain diseases. However, their efficacy in recapitulating brain network properties that encode brain function remains limited, thereby precluding development of effective in vitro models of complex brain disorders like schizophrenia. Here, we develop and characterize a Modular Neuronal Network (MoNNet) approach that recapitulates specific features of neuronal ensemble dynamics, segregated local-global network activities and a hierarchical modular organization. We utilized MoNNets for quantitative in vitro modelling of schizophrenia-related network dysfunctions caused by highly penetrant mutations in SETD1A and 22q11.2 risk loci. Furthermore, we demonstrate its utility for drug discovery by performing pharmacological rescue of alterations in neuronal ensembles stability and global network synchrony. MoNNets allow in vitro modelling of brain diseases for investigating the underlying neuronal network mechanisms and systematic drug discovery.
3D 神经元培养技术的进步，如脑球体和类器官，正在为研究大脑疾病的分子、细胞和发育机制提供前所未有的体外方法。然而，它们在再现编码大脑功能的大脑网络特性方面的效果仍然有限，从而阻碍了复杂大脑疾病（如精神分裂症）的有效体外模型的发展。在这里，我们开发并描述了一种模块化神经元网络（MoNNet）方法，该方法可以再现神经元集合动力学、局部-全局网络活动和分层模块化组织的特定特征。我们利用 MoNNets 对 SETD1A 和 22q11.2 风险基因座的高穿透性突变引起的与精神分裂症相关的网络功能障碍进行定量的体外建模。此外，我们通过对神经元集合稳定性和全局网络同步性的改变进行药理学恢复，证明了其在药物发现中的应用。MoNNets 允许对脑疾病进行体外建模，以研究潜在的神经元网络机制和系统药物发现。
