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

患者源性神经元中精神病的离体特征和治疗反应

• 批准号: 9896850
• 负责人: Rakesh Karmacharya
• 金额: $ 54.5万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896850
• 关键词: AKT Signaling Pathway; Address; Animal Model; Antipsychotic Agents; Autopsy; Biological Assay; Biology; Bipolar Disorder; Bipolar Neuron; Brain; Categories; Cell Line; Clinical; Clinical Treatment; Clozapine; Data; Dendritic Spines; Development; Diagnostic; Exposure to; Frequencies; Health; Human; Image; In Vitro; Institutional Review Boards; Mediating; Mental disorders; Methods; Microscopy; Molecular; Neurobiology; Neurons; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Prediction of Response to Therapy; Prefrontal Cortex; Prosencephalon; Psychiatry; Psychotic Disorders; Reagent; Resolution; Rodent; Role; Schizophrenia; Synapses; Testing; Treatment Efficacy; Vertebral column; base; brain tissue; density; disability; hippocampal pyramidal neuron; human pluripotent stem cell; human subject; in vivo; induced pluripotent stem cell; novel; novel therapeutic intervention; phosphoproteomics; responders and non-responders; response; treatment response

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.

项目摘要 精神障碍的有效治疗仍然是精神病学的一个重大挑战。电流 治疗方法依赖于几十年前偶然发现的化合物， 迫切需要针对精神病神经生物学的新治疗方法。尸体解剖研究 精神分裂症和精神病性双相情感障碍提示树突棘异常在 前额叶皮层（PFC）在精神病中的作用。精神病患者的大脑显示出复制良好的神经元 树突棘密度异常，特别是在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中树突棘突触减少， 在上层皮层神经元中的显著效果。此外，在这些脊髓中， 用抗精神病药物治疗逆转动物模型。体外培养啮齿类动物神经元的研究表明， 抗精神病药物氯氮平调节树突棘，两项独立的研究表明， 树突棘密度与氯氮平治疗啮齿类动物神经元。这些研究提供了强大的动力， 测试树突棘生物学在生物学和治疗中起重要作用的假设， 精神病迄今为止的研究主要集中在死后大脑，动物模型和啮齿动物神经元 cultures.为了扩展这些发现，我们试图研究由精神病患者产生的皮层神经元， 紊乱我们已经重新编程了来自人类受试者的诱导多能干细胞（iPSC）， 精神分裂症和双相情感障碍以及匹配的健康对照。我们区分了人类 iPSC沿着前脑谱系以产生成熟的皮质神经元。根据我们的初步研究 患者源性神经元和氯氮平对树突棘密度的影响，我们假设， 从患有精神障碍的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种神经元相比，密度。我们进一步假设， 体外将有不同的影响树突棘密度神经元来源于病人谁是氯氮平 与氯氮平无应答者相比，