Mitochondrial Dysfunction In Schizophrenia

精神分裂症的线粒体功能障碍

• 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
• 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

 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（通过应用程序证明）：线粒体几乎提供了突触传播的所有能量，在突触中的离子稳态，神经元素的发育和长期增强的能量。 对于这些神经元的作用，mitchondria细胞的存活，对氧化应激源反应，并为大多数细胞功能提供ATP。 ATP的分子在我们的最初授予中，我们发现了躁郁症的精神分裂症功能障碍的有力证据。在精神分裂症中，与对照相比，在躁郁症中，我们假设了多基因模型。 MTDNA含量是遗传性的，在遗传控制下，我们还将在精神分裂症的慢性受试者中测试MTDNA含量与精神分裂症的症状。与对照组相比，树突和轴突中的米奇氏菌的定位和副本数量。大脑，我们对验尸大脑的研究将精神分裂症的受试者提供给无药物。与对照组相比，在慢性治疗的恒河体功能上，慢性治疗的大脑会在fibbroveblast-dection shemblant op Psychiss中比较fibbroveblast rocky of Contrests Psychiss o f比较这项研究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