Teng Ziwei, Chen Zhuohui, Zou Tianxiang, Su Yuhan, Zeng Hongtao, Sun Shixiong, Chen Haiyu, Liu Jieyu, Qin Yue, Wu Haishan, Chen Jindong, Liu Fangkun, Wu Renrong, Huang Jing
Department of Psychiatry, National Clinical Research Center for Mental Disorders, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
Department of Psychiatry, Clinical Research Center for Depressive Disorder in Hunan Province, The Second People's Hospital of Hunan Province (Brain Hospital of Hunan Province), Changsha 410007, China.
iScience. 2024 Sep 11;27(10):110917. doi: 10.1016/j.isci.2024.110917. eCollection 2024 Oct 18.
The portrayed effects of olanzapine on brain development and neuronal response remain unclear under the genetic background of . Here, we constructed therapeutic-dosage olanzapine-treated cerebral organoid (CO) models using induced pluripotent stem cells from human samples. We found that the activation of NODAL/FOXH1 axis mediated the early response to olanzapine up to day 15, which subsequently caused thicker cortical-like structures, cell identity maturation, higher stemness of neural progenitor cells (NPCs), and mature neuronal firing of early neurons in day 24. Transcriptomics and targeted metabolomics confirmed the upregulation of neurodevelopmental-related terms and glutamate production on day 24. Gene enrichment of transcriptomics into large-scale genome-wide association studies (GWAS) showed possible relationships with intelligence, major depressive disorder, schizophrenia. We did not observe the negative effects of exposure to olanzapine in mice. Collectively, we tended to conclude that olanzapine treatment had beneficial effects instead of harmful on early brain development.
在……的遗传背景下，奥氮平对大脑发育和神经元反应的影响尚不明确。在此，我们使用来自人类样本的诱导多能干细胞构建了治疗剂量奥氮平处理的脑类器官（CO）模型。我们发现，NODAL/FOXH1轴的激活介导了直至第15天对奥氮平的早期反应，这随后导致了更厚的皮质样结构、细胞身份成熟、神经祖细胞（NPC）更高的干性以及第24天早期神经元的成熟神经元放电。转录组学和靶向代谢组学证实了第24天神经发育相关术语和谷氨酸产生的上调。将转录组学基因富集到大规模全基因组关联研究（GWAS）中显示出与智力、重度抑郁症、精神分裂症的可能关系。我们未观察到奥氮平暴露对小鼠的负面影响。总体而言，我们倾向于得出结论，奥氮平治疗对早期大脑发育具有有益而非有害的影响。
