Abstract：
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.
摘要：
伴有自杀行为的重度抑郁症（sMDD）是一种服务器情绪障碍，给家庭和社会带来巨大负担。尽管在sMDD患者的死后组织中观察到γ-氨基丁酸（GABA）水平降低，GABA水平改变的分子机制仍然难以捉摸。在这项研究中,我们从5例sMDD患者中产生了诱导多能干细胞(iPSC),并将iPSC分化为GABA能中间神经元(GINs)和腹侧前脑类器官.sMDDGINs表现出神经元形态改变和神经放电增加，以及减弱的钙信号传播，与对照组相比。转录组测序显示，5-羟色胺能受体2C（5-HT2C）的表达降低可能会导致sMDD中神经元活性缺陷。此外，靶向5-HT2C受体，使用小分子激动剂或遗传方法，恢复sMDDGINs的神经元活性缺陷。我们的发现为研究sMDD的分子机制和药物发现提供了人类细胞模型。
