Ultrastructure of the hippocampal trisynaptic pathway in schizophrenia

精神分裂症海马三突触通路的超微结构

• 批准号: 10294349
• 负责人: Rosalinda C Roberts
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10294349
• 关键词: Affect; Antipsychotic Agents; Area; Autopsy; Brain; Cells; Cessation of life; Clinic; Data; Dendritic Spines; Disease; Electron Microscopy; Electrons; Environmental Risk Factor; Excitatory Synapse; Functional disorder; Future; Genetic Risk; Glutamates; Hippocampus (Brain); Human; Hyperactivity; Impairment; Inhibitory Synapse; Interneurons; Intervention; Location; Measures; Mental disorders; Methods; Microscopic; Mitochondria; Morphology; Neural Network Simulation; Neurons; Neuropil; Neurotransmitters; Pathologic; Pathology; Pathway interactions; Patients; Perforant Pathway; Physical shape; Physiology; Play; Population; Presynaptic Terminals; Psychoses; Pyramidal Cells; Role; Sample Size; Sampling; Schizophrenia; Severities; Source; Stratum Lucidum; Structure; Structure of molecular layer of cerebellar cortex; Study models; Symptoms; Synapses; System; Testing; Tissues; Work; cohort; comparison group; density; dentate gyrus; effective therapy; entorhinal cortex; experimental study; granule cell; gray matter; in vivo imaging; mossy fiber; neuroimaging; neuronal cell body; neuropathology; pre-clinical; white matter

Schizophrenia (SZ) is a devastating mental illness with genetic and environmental risk factors that affects 1% of the world population. Pathology exists in multiple grey and white matter areas and neurotransmitter systems, making the search for a cause(s) and effective treatment elusive. Exploring new pathological mechanisms is paramount in trying to advance our understanding of SZ. The hippocampus is considered to play a pivotal role in the neuropathology and physiology of schizophrenia. Though widely studied, there have been inconsistencies in which subregions, neurotransmitters and cell populations are affected; thus how specific subregion abnormalities contribute to disease expression remain to be fully determined. This proposal aims to identify the circuitry that contribute to region-specific imbalances in excitation and inhibition in the hippocampus in schizophrenia. Here, we propose to test whether there are region-specific differences in the excitatory and inhibitory synapses in the trisynaptic pathway in postmortem tissue of patients with schizophrenia compared to a comparison group using quantitative electron microscopy. My overall hypothesis is two fold: 1) synaptic efficacy of excitatory synapses is enhanced by increased number or size of synapses or increased mitochondrial content in the terminals forming these synapses; and 2) the synaptic efficacy of inhibitory synapses in diminished by decreased number or size of synapses or decreased mitochondrial content in the terminals forming these synapses. Preclinical and clinic data indicate hyperactivity in the hippocampus that precedes the onset of psychosis, and which is correlated with the severity of symptoms. In our preliminary data, we have observed increased numbers of excitatory synapses and decreased number of inhibitory synapses, identified by morphological criteria. SA1) In postmortem brain, we will test the hypothesis that SZ cases have decreased efficacy of inhibitory synapses and an increased efficacy of excitatory synapses in the trisynaptic pathway by counting, measuring and categorizing the morphology of synapses and the mitochondria within the terminals forming them. SA2) To determine the synaptic density on the neuronal somata in the trisynaptic pathway. By examining the exact laminar location of excitatory inputs we will be able to determine the sources of abnormal circuitry. Electron microscopy offers the unique opportunity to measure hippocampal subfields in a layer and cell specific way at the level of the synapse. The source of afferent inputs to specific subfields and layers, the density of specific inputs, and the ultrastructural features of the axon terminals, the experiments in this application have the potential to reveal specific circuitry underlying hyperactivity in the hippocampus in schizophrenia and guide future tests of region and/or cell-specific interventions. Quantitative electron microscopic studies of the human postmortem hippocampus in schizophrenia currently are performed in only one other lab in the world. Our results on the ultrastructural results will have distinct functional implications for schizophrenia as well as for normal human hippocampal circuitry.

精神分裂症（SZ）是一种具有遗传和环境风险因素的破坏性精神疾病， 占世界人口的1%。病理存在于多个灰质和白色质区域及神经递质 系统，使得寻找原因和有效的治疗难以捉摸。探索新的病理 机制是最重要的，试图提高我们对深圳的理解。海马体被认为是发挥 在精神分裂症的神经病理学和生理学中起着关键作用。虽然被广泛研究， 不一致的亚区域，神经递质和细胞群受到影响;因此，如何具体 亚区异常对疾病表达的贡献仍有待充分确定。这项建议旨在 确定导致海马体中兴奋和抑制的区域特异性失衡的电路 精神分裂症在这里，我们建议测试是否有区域特异性差异的兴奋性和 精神分裂症患者死后组织中三突触通路中的抑制性突触， 使用定量电子显微镜的对照组。我的总体假设是两个方面：1）突触功效 兴奋性突触的数量或大小增加或线粒体含量增加 在形成这些突触的终端;和2）抑制性突触的突触功效减少， 突触数量或大小减少，或形成这些突触的终末中线粒体含量减少 突触临床前和临床数据表明，在海马体中的过度活跃， 精神病，并与症状的严重程度相关。在我们的初步数据中， 兴奋性突触数量增加，抑制性突触数量减少，通过 形态学标准SA 1）在死后的大脑中，我们将检验SZ病例减少的假设 三突触通路中抑制性突触的功效和兴奋性突触的增加的功效， 对突触和终末内线粒体的形态进行计数、测量和分类 形成它们。SA 2）确定三突触通路中神经元胞体上的突触密度。通过 检查兴奋性输入的确切层位置，我们将能够确定异常的来源。 电路电子显微镜提供了独特的机会来测量海马子领域在一个层， 细胞特异性的方式在突触的水平。特定子字段和层的传入输入源， 特异性输入的密度和轴突终末的超微结构特征， 有可能揭示精神分裂症患者海马体活动过度的特定回路， 指导区域和/或细胞特异性干预的未来测试。电子显微镜定量研究 目前，世界上只有另一个实验室对精神分裂症患者的死后海马体进行了研究。 我们的结果对超微结构的结果将有不同的功能意义，精神分裂症以及 正常的人类海马电路