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 在精神病学中，有效的精神病治疗仍然是一个重大挑战。当前的 治疗方法依赖于几十年前偶然发现的化合物，并且有一个 迫切需要针对精神病神经生物学的新治疗方法。验尸研究 精神分裂症和精神病性躁郁症表明树突状脊柱异常在 精神病的前额叶皮层（PFC）。精神病患者的大脑表现出良好的神经元 树突状脊柱密度的异常，特别是在上层皮质锥体神经元中。另外，在 精神病动物模型，脑组织显示PFC中的树突状脊柱突触降低，更多 在上层皮质神经元中明显效应。此外，脊柱突触的减少 动物模型通过抗精神病药物逆转。培养啮齿动物神经元的体外研究表明 抗精神病药氯氮平调节树突状刺，两项独立研究表明增加 通过氯氮平治疗的啮齿动物神经元中的树突状脊柱密度。这些研究为 检验以下假设，即树突状脊柱生物学在生物学和处理中起重要作用 精神病。迄今为止的研究集中在尸体后大脑，动物模型和啮齿动物神经元上 文化。为了扩展这些发现，我们试图研究由精神病患者产生的皮质神经元 疾病。我们已经重编程了来自人类受试者的多能干细胞（IPSC） 精神分裂症和躁郁症以及匹配的健康对照组。我们有分歧 沿前脑谱系的IPSC产生成熟的皮质神经元。基于我们对 患者衍生的神经元和氯氮平对树突状脊柱密度的影响，我们假设 由患有精神病患者产生的层皮质神经元将显示树突状脊柱降低 与健康受试者的此类神经元相比，密度。我们进一步假设氯氮平暴露在 体外将对来自氯氮平患者的神经元的树突状脊柱密度有不同的影响 与氯氮平无反应器相比，响应者。