Ex vivo signature of psychosis and treatment response in patient-derived neurons

项目总结 精神障碍的有效治疗仍然是精神病学的一个重大挑战。当前 治疗方法依赖于几十年前偶然发现的化合物，而且有一种 迫切需要针对精神病的神经生物学的新的治疗方法。身体解剖研究 精神分裂症和精神病性双相情感障碍提示树突棘异常在 精神病患者的前额叶皮质。精神障碍患者的大脑显示复制良好的神经元 树突棘密度异常，尤其是上层皮质锥体神经元。此外，在 在精神病动物模型中，脑组织显示PFC中的树突突触减少，具有更多 对上层皮质神经元有明显的影响。此外，这些神经元中脊椎突触的减少 动物模型被抗精神病药物治疗逆转。对培养的啮齿动物神经元的体外研究表明 抗精神病药物氯氮平调节树突棘，两项独立研究表明 氯氮平处理的啮齿动物神经元中树突棘密度。这些研究提供了强大的推动力 验证树突棘生物学在肿瘤的生物学和治疗中发挥重要作用的假设 精神错乱。到目前为止，这些研究主要集中在死后大脑、动物模型和啮齿动物神经元上。 文化。为了扩展这些发现，我们试图研究精神病患者的大脑皮层神经元。 精神错乱。我们对人类受试者的诱导多能干细胞(IPSCs)进行了重新编程 精神分裂症和双相情感障碍以及相匹配的健康对照。我们已经将人类 IPSCs沿着前脑谱系产生成熟的皮质神经元。基于我们对以下方面的初步研究 患者来源的神经元和氯氮平对树突棘密度的影响，我们假设上- 精神障碍受试者产生的皮层神经元将显示树突棘减少 与来自健康受试者的这些神经元的密度进行比较。我们进一步假设氯氮平在 体外培养将对氯氮平患者神经元树突棘密度产生不同的影响 有效者与氯氮平无应答者相比。

PROJECT SUMMARY The efficacious treatment of psychotic disorders remains a significant challenge in psychiatry. Current treatment approaches rely on compounds discovered serendipitously many decades ago and there is an urgent need for new therapeutic approaches that target the neurobiology of psychosis. Postmortem studies of schizophrenia and psychotic bipolar disorder suggest a significant role for dendritic spine abnormalities in the prefrontal cortex (PFC) in psychosis. Brains of patients with psychotic disorders show well-replicated neuronal abnormalities in dendritic spine density, specifically in upper-layer cortical pyramidal neurons. Additionally, in animal models of psychosis, brain tissue show decreased dendritic spine synapses in the PFC, with a more pronounced effect in the upper-layer cortical neurons. Furthermore, the decrease in spine synapses in these animal models was reversed with antipsychotic treatment. In vitro studies of cultured rodent neurons show that the antipsychotic clozapine modulates dendritic spines, with two independent studies showing increase in dendritic spine density in rodent neurons with clozapine treatment. These studies provide a strong impetus to test the hypothesis that dendritic spine biology plays an important role in the biology and treatment of psychosis. The studies to date have focused on postmortem brains, animal models and rodent neuronal cultures. To extend these findings, we seek to study cortical neurons generated from subjects with psychotic disorders. We have reprogrammed induced pluripotent stem cells (iPSCs) from human subjects with schizophrenia and bipolar disorder as well as from matched healthy controls. We have differentiated human iPSCs along the forebrain lineage to generate mature cortical neurons. Based on our preliminary studies of patient-derived neurons and of the effects of clozapine on dendritic spine density, we hypothesize that upper- layer cortical neurons generated from subjects with psychotic disorders will show decreased dendritic spine density compared to such neurons from healthy subjects. We further hypothesize that clozapine exposure in vitro will have differential effects on dendritic spine density in neurons derived from patients who are clozapine responders when compared to clozapine non-responders.