Antipsychotics are known to modulate dopamine and other neurotransmitters which is often thought to be the mechanism underlying their therapeutic effects. Nevertheless, other less studied consequences of antipsychotics on neuronal function may contribute to their efficacy. Revealing the complete picture behind their action is of paramount importance for precision medicine and accurate drug selection. Progress in cell engineering allows the generation of induced pluripotent stem cells (iPSCs) and their differentiation to a variety of neuronal types, providing new tools to study antipsychotics. Here we use excitatory cortical neurons derived from iPSCs to explore their response to therapeutic levels of Clozapine as measured by their transcriptomic output, a proxy for neuronal homeostasis. To our surprise, but in agreement with the results of many investigators studying glial-like cells, Clozapine had a very strong effect on cholesterol metabolism. More than a quarter (12) of all annotated cholesterol genes (46) in the genome were significantly changed at FDR<0.1, all upregulated. This is a 35-fold enrichment with an adjusted p = 8 x10-11. Notably no other functional category showed evidence of enrichment. Cholesterol is a major component of the neuronal membrane and myelin but it does not cross the blood brain barrier, it is produced locally mostly by glia but also by neurons. By singling out increased expression of cholesterol metabolism genes as the main response of cortical excitatory neurons to antipsychotics, our work supports the hypothesis that cholesterol metabolism may be a contributing mechanism to the beneficial effects of Clozapine and possibly other antipsychotics

中文翻译：

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人类诱导的兴奋神经元的转录组分析支持氯氮平对胆固醇生物合成的强大作用

已知抗精神病药可调节多巴胺和其他神经递质，这通常被认为是其治疗作用的基础。然而，抗精神病药对神经元功能的其他较少研究的结果可能有助于其功效。揭示其作用背后的完整画面对于精确医学和精确药物选择至关重要。细胞工程技术的进步允许诱导多能干细胞（iPSC）的产生及其向多种神经元类型的分化，从而为研究抗精神病药提供了新的工具。在这里，我们使用源自iPSC的兴奋性皮质神经元来探索其对氯氮平治疗水平的反应，该反应通过其转录组输出（神经元稳态的替代物）来衡量。令我们惊讶的是 但是，与许多研究神经胶质样细胞的研究者的结果一致，氯氮平对胆固醇代谢具有非常强的作用。在FDR <0.1的情况下，基因组中所有注释的胆固醇基因（46）中有超过四分之一（12）发生了显着变化，均被上调。这是35倍富集，调整后的p = 8 x10-11。值得注意的是，没有其他功能类别显示出富集的迹象。胆固醇是神经元膜和髓磷脂的主要成分，但它不穿过血脑屏障，它主要由神经胶质产生，也由神经元产生。通过挑选出胆固醇代谢基因表达的增加作为皮质兴奋性神经元对抗精神病药的主要反应，