Mitochondrial Dysfunction In Schizophrenia

精神分裂症的线粒体功能障碍

基本信息

批准号：
9030483
负责人：
MARQUIS PHILIP VAWTER
金额：
$ 73.95万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9030483
关键词：
Accounting Address Age Anhedonia Antipsychotic Agents Apical Auditory Autopsy Axon Biological Assay Bipolar Disorder Blood Blood Cell Count Blood specimen Brain Brain region Cell Survival Cell physiology Cessation of life Chronic Chronic Schizophrenia Clinical Research Control Groups DNA DNA copy number Data Dendrites Enrollment Fibroblasts Fluorescence Functional disorder Gene Expression Genes Genetic Genotype Grant Haplogroup Heritability Homeostasis Human In Vitro Individual Investigation Knowledge Location Long-Term Potentiation Macaca mulatta Maintenance Measures Membrane Potentials Meta-Analysis Mitochondria Mitochondrial DNA Modeling Neurobehavioral Manifestations Neurons North America Nuclear Nucleus Accumbens Outcome Study Pharmaceutical Preparations Pharmacotherapy Phenotype Ploidies Prefrontal Cortex Presynaptic Terminals Psychotic Disorders Reporting Resolution Role Schizophrenia Site Smoking Somatic Mutation Specificity Staging Study Subject Superior temporal gyrus Symptoms Synapses Synaptic Transmission Technology Testing Time Transcript Variant Vertebral column Visual Cortex Visual Hallucination base brain cell cell motility cohort density exome first episode psychosis follow-up genome wide association study hippocampal pyramidal neuron induced pluripotent stem cell mitochondrial dysfunction mitochondrial membrane neuron development nonhuman primate novel postsynaptic psychiatric symptom public health relevance relating to nervous system sex stressor trait treatment response

项目摘要

DESCRIPTION (provided by applicant): Mitochondria provide nearly all of the energy for synaptic transmission, maintenance of ionic homeostasis in synaptic terminals, development of neuronal spines, and long term potentiation which are all essential for brain function. In addition to these neuronal roles, mitochondria regulate cell survival, react to oxidative stressors, and provide ATP for most cellular functions. It is estimated that a single cortical neuron utilizes 109 molecules of ATP each second. In our initial grant, we found strong evidence of mitochondria dysfunction in schizophrenia, compared to weaker evidence for dysfunction in bipolar disorder. We conservatively estimated mitochondria DNA content heritability (h2 = 0.37), and found a highly significant decrease of mitochondria DNA in schizophrenia compared to controls and bipolar disorder. Our studies have also shown decreased gene expression and common deletion, in schizophrenia, but not in bipolar disorder, compared to controls. We have postulated a polygenic model that nuclear and mitochondrial genes interact to alter mitochondria content in periphery and in brain. This decrease in mitochondria in brain, could account for significant decreases in density of spines, especially prominent in layer III. We will further test this model, that mtDNA content is heritable, and under genetic control. We will also test association of mtDNA content with symptoms of schizophrenia. Since our initial studies have been conducted in chronic subjects with schizophrenia, we are renewing our grant to study subjects with first episode psychosis for evidence of the mitochondria dysfunction before onset of antipsychotic drug treatments. The overarching hypothesis is that the pathophysiology of SZ is associated with a reduction in mitochondrial function specifically in the localization and copy number of mitochondria in dendrite and axon locations compared to controls. The cause of the dysfunction postulated in our model is polygenic variation in both nuclear and mitochondrial genes that contribute to mitochondria copy number trait and function. We will test for association of mitochondria DNA copy number in both nuclear and mitochondrial SNPs in first episode psychosis and chronic psychosis, using blood and postmortem brain, and extend our investigations of postmortem brain to medication free individuals with schizophrenia, including bipolar disorder subjects for specificity of findings. To be confident that chronic treatment with antipsychotic drugs (APDs) does not alter mitochondria localization, we propose to study a cohort of non-human primate brains at cellular resolution, already chronically treated with APDs. Since synaptic terminal activity is dependent upon mitochondria function, we will compare the numbers of mitochondria located in postsynaptic spines in individuals with schizophrenia and controls, and APD treated rhesus monkeys compared to controls. Finally, we will assess whether APD treatment alters mitochondrial copy number, intraneuronal motility, and membrane potential in fibroblast-induced pluripotent stem cells reprogrammed into neurons from first episode psychosis subjects compared to controls. The outcomes of this study will expand our knowledge of genetic basis for mitochondria dysfunction in schizophrenia, and association of that dysfunction with psychiatric symptoms.

描述（应用程序提供）：线粒体几乎提供了突触传播的所有能量，在突触末端维持离子稳态，神经脊柱的发展以及对大脑功能至关重要的长期潜在。此外对于这些神经元的作用，线粒体调节细胞存活，对氧化物胁迫反应，并为大多数细胞功能提供ATP。据估计，单个皮质神经元使用109 ATP分子每秒。在我们的最初赠款中，我们发现了精神分裂症线粒体功能障碍的有力证据，与双相情感障碍功能障碍的较弱的证据相比。我们保守地估计了线粒体DNA含量的遗传力（H2 = 0.37），并且与对照组和双相情感障碍相比，精神分裂症中线粒体DNA的高度降低。我们的研究还表明，与对照组相比，在精神分裂症中，基因表达和共同缺失降低，但在躁郁症中却没有。我们发布了一个多基因模型，即核和线粒体基因相互作用以改变外周和大脑中的线粒体含量。这种大脑线粒体的下降可能是棘突密度的显着下降，尤其是第三层。我们将进一步测试此模型 mtDNA含量是可遗传的，并且在遗传控制下。我们还将测试mtDNA含量与精神分裂症症状的关联。由于我们的最初研究是在精神分裂症的慢性受试者中进行的，因此我们正在续签授予第一事件精神病的受试者，以证明抗精神病药治疗发作之前线粒体功能障碍的证据。总体假设是，与对照组相比，SZ的病理生理学与线粒体功能的降低相关，该线粒体功能特别是在树突和轴突位置的线粒体的定位和拷贝数。我们模型中假定的功能障碍的原因是核和线粒体基因的多基因变异，这些变化有助于线粒体拷贝数特征和功能。我们将使用血液和验尸大脑在第一事件精神病和慢性精神病中测试线粒体DNA拷贝数在核和线粒体SNP中的关联，并将我们对后脑大脑后脑大脑的研究扩展到无与伦比的精神分裂症患者，包括双极疾病，包括双极疾病的特定性。为了确信用抗精神病药（APD）的慢性治疗不会改变线粒体定位，我们建议研究细胞分辨率的非人类灵长类动物大脑的队列，该分辨率已经经过了APD的长期处理。突触终末活性取决于线粒体功能，我们将比较精神分裂症和对照组中突触后棘的线粒体的数量，与对照组相比，APD治疗的恒河猴治疗了。最后，我们将评估APD治疗在成纤维细胞诱导的多能干细胞中是否会改变线粒体拷贝数，鼻内神经元运动和膜电位是否会与对照组相比重新编程为神经元中的神经元。这项研究的结果将扩大我们对精神分裂症线粒体功能障碍的遗传基础的了解，并将这种功能障碍与精神病症状的关联。