Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
NORMENT, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Mol Psychiatry. 2023 Jul;28(7):3033-3043. doi: 10.1038/s41380-023-01944-0. Epub 2023 Jan 18.
Lithium (Li) is recommended for long-term treatment of bipolar disorder (BD). However, its mechanism of action is still poorly understood. Induced pluripotent stem cell (iPSC)-derived brain organoids have emerged as a powerful tool for modeling BD-related disease mechanisms. We studied the effects of 1 mM Li treatment for 1 month in iPSC-derived human cortical spheroids (hCS) from 10 healthy controls (CTRL) and 11 BD patients (6 Li-responders, Li-R, and 5 Li non-treated, Li-N). At day 180 of differentiation, BD hCS showed smaller size, reduced proportion of neurons, decreased neuronal excitability and reduced neural network activity compared to CTRL hCS. Li rescued excitability of BD hCS neurons by exerting an opposite effect in the two diagnostic groups, increasing excitability in BD hCS and decreasing it in CTRL hCS. We identified 132 Li-associated differentially expressed genes (DEGs), which were overrepresented in sodium ion homeostasis and kidney-related pathways. Moreover, Li regulated secretion of pro-inflammatory cytokines and increased mitochondrial reserve capacity in BD hCS. Through long-term Li treatment of a human 3D brain model, this study partly elucidates the functional and transcriptional mechanisms underlying the clinical effects of Li, such as rescue of neuronal excitability and neuroprotection. Our results also underscore the substantial influence of treatment duration in Li studies. Lastly, this study illustrates the potential of patient iPSC-derived 3D brain models for precision medicine in psychiatry.
锂（Li）被推荐用于长期治疗双相情感障碍（BD）。然而，其作用机制仍不清楚。诱导多能干细胞（iPSC）衍生的脑类器官已成为模拟与 BD 相关的疾病机制的有力工具。我们研究了在 10 名健康对照者（CTRL）和 11 名 BD 患者（6 名 Li 反应者，Li-R 和 5 名 Li 未治疗者，Li-N）的 iPSC 衍生的人类皮质球体（hCS）中，1mM Li 治疗 1 个月的影响。在分化的第 180 天，BD hCS 比 CTRL hCS 体积更小，神经元比例降低，神经元兴奋性降低，神经网络活性降低。Li 通过在两个诊断组中发挥相反的作用来挽救 BD hCS 神经元的兴奋性，增加 BD hCS 神经元的兴奋性，降低 CTRL hCS 神经元的兴奋性。我们鉴定出 132 个与 Li 相关的差异表达基因（DEG），这些基因在钠离子稳态和肾脏相关途径中过度表达。此外，Li 调节了 BD hCS 中促炎细胞因子的分泌，并增加了其线粒体储备能力。通过对人类 3D 脑模型进行长期 Li 治疗，本研究部分阐明了 Li 临床疗效的功能和转录机制，例如挽救神经元兴奋性和神经保护。我们的研究结果还强调了 Li 研究中治疗持续时间的重要影响。最后，本研究说明了患者 iPSC 衍生的 3D 脑模型在精神医学精准医学中的潜力。
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