神经发育障碍 (NDD) 包括一系列以大脑发育异常以及认知、情绪和行为功能受损为特征的疾病。转基因动物模型（主要是啮齿动物）传统上是破译 NDD 病理生理学分子机制的关键工具，并为旨在治疗这些疾病的药物干预措施的发展做出了重大贡献。然而，这些治疗方法对人类的疗效已被证明是有限的，部分原因是动物模型难以概括人脑的复杂发育和结构，而且还由于受影响个体之间发现的表型异质性。诱导多能干细胞（iPSC）领域的重大进展为克服这些挑战提供了一条有希望的途径。事实上，用于生成 iPSC 衍生脑类器官的先进分化方案的开发为探索人类神经发育提供了前所未有的机会。本综述概述了如何使用 3D 脑类器官来研究各种 NDD（即脆性 X 综合征、Rett 综合征、Angelman 综合征、微无脑畸形、普瑞德威利综合征、蒂莫西综合征、结节性硬化症综合征），并阐明其病理生理学。我们还讨论了在个性化医疗领域，与动物模型和 2D 细胞培养系统相比，采用此类创新 3D 模型的好处和局限性。© 作者 2024。由牛津大学出版社代表 Brain 担保人出版。

Neurodevelopmental disorders (NDD) encompass a range of conditions marked by abnormal brain development in conjunction with impaired cognitive, emotional, and behavioural functions. Transgenic animal models, mainly rodents, traditionally served as key tools for deciphering the molecular mechanisms driving NDD physiopathology, and significantly contributed to the development of pharmacological interventions aimed at treating these disorders. However, the efficacy of these treatments in humans has proven to be limited, due in part to the intrinsic constraint of animal models to recapitulate the complex development and structure of the human brain but also to the phenotypic heterogeneity found between affected individuals. Significant advancements in the field of induced pluripotent stem cells (iPSC) offer a promising avenue for overcoming these challenges. Indeed, the development of advanced differentiation protocols for generating iPSC-derived brain organoids gives the unprecedented opportunity to explore the human neurodevelopment. This review provides an overview of how 3D brain organoids have been used to investigate various NDD (i.e., Fragile X syndrome, Rett syndrome, Angelman syndrome, microlissencephaly, Prader-Willi syndrome, Timothy Syndrome, tuberous sclerosis syndrome), and elucidate their pathophysiology. We also discuss the benefits and limitations of employing such innovative 3D models compared to animal models and 2D cell culture systems, in the realm of personalized medicine.© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.