Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China.
Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China.
EMBO Mol Med. 2023 Jan 11;15(1):e16364. doi: 10.15252/emmm.202216364. Epub 2022 Nov 14.
Major depressive disorder with suicide behavior (sMDD) is a server mood disorder, bringing tremendous burden to family and society. Although reduced gamma amino butyric acid (GABA) level has been observed in postmortem tissues of sMDD patients, the molecular mechanism by which GABA levels are altered remains elusive. In this study, we generated induced pluripotent stem cells (iPSC) from five sMDD patients and differentiated the iPSCs to GABAergic interneurons (GINs) and ventral forebrain organoids. sMDD GINs exhibited altered neuronal morphology and increased neural firing, as well as weakened calcium signaling propagation, compared with controls. Transcriptomic sequencing revealed that a decreased expression of serotoninergic receptor 2C (5-HT2C) may cause the defected neuronal activity in sMDD. Furthermore, targeting 5-HT2C receptor, using a small molecule agonist or genetic approach, restored neuronal activity deficits in sMDD GINs. Our findings provide a human cellular model for studying the molecular mechanisms and drug discoveries for sMDD.
伴有自杀行为的重度抑郁症（sMDD）是一种严重的情绪障碍，给家庭和社会带来了巨大的负担。尽管在 sMDD 患者的尸检组织中观察到γ-氨基丁酸（GABA）水平降低，但 GABA 水平改变的分子机制仍不清楚。在这项研究中，我们从五名 sMDD 患者中生成诱导多能干细胞（iPSC），并将 iPSC 分化为 GABA 能中间神经元（GIN）和腹侧前脑类器官。与对照组相比，sMDD GIN 表现出神经元形态改变和神经放电增加，以及钙信号传播减弱。转录组测序显示，5-羟色胺能受体 2C（5-HT2C）表达降低可能导致 sMDD 中神经元活动的缺陷。此外，使用小分子激动剂或遗传方法靶向 5-HT2C 受体，可以恢复 sMDD GIN 中的神经元活动缺陷。我们的研究结果为研究 sMDD 的分子机制和药物发现提供了一个人类细胞模型。
