Morphological Alterations of Cortical Layer 3 Pyramidal Cells in Schizophrenia

精神分裂症中皮质第 3 层锥体细胞的形态改变

• 批准号: 9355834
• 负责人: ROBERT A SWEET
• 金额: --
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9355834
• 关键词: Actins; Address; Alcohol or Other Drugs use; Alcohols; Attention; Behavior; Binding; Brain region; Cells; Cellular Morphology; Cognition; Data; Dendritic Spines; Disease; Exhibits; Fluorescence; Future; Glutamates; Impairment; Individual; Instruction; Label; Link; Measures; Metabolic Marker; Mind; Modeling; Molecular; Morphology; Myoepithelial cell; Nature; Neurons; Parietal; Parietal Lobe; Parvalbumins; Pathology; Pharmaceutical Preparations; Prefrontal Cortex; Process; Protein Isoforms; Proteins; Pyramidal Cells; Reporting; Schizophrenia; Severities; Short-Term Memory; Specificity; Structure; Synapses; Synapsins; Synaptophysin; Testing; Thalamic structure; Toxin; Visual; Visual Cortex; activity marker; area striata; base; cell type; cytochrome c oxidase; density; design; glutamate decarboxylase GAD67; human subject; immunoreactivity; information processing; mRNA Expression; molecular marker; neuroimaging; neuronal cell body; nonhuman primate; novel; protein biomarkers; spinophilin; suicidal morbidity; vesicular glutamate transporter 1

The Center's Central Hypothesis posits that layer 3 pyramidal cells (PCs) in subjects with schizophrenia have a cell type-autonomous pathology that is refiected in altered somatodendritic morphology and that differs in severity across regions in the cortical visual working memory and attention network. These abnormalities of layer 3 PCs result in locally reduced excitatory drive, refiected in reduced markers of metabolic activity in layer 3 PCs and reduced activity-dependent markers in reciprocally-connected layer 3 parvalbumin (PV)-expressing basket cells. This model leads to several novel predicfions. For example, that deflcits in layer 3 PC somal volume and dendritic spine density are present in mulfiple cortical regions, but moderated by region-specific factors (Aim 1). To date only limited analyses of primary visual cortex (VI) have been conducted, and the posterior parietal cortex (PPC) has not been examined. Our preliminary data indicate that impairments in dorsolateral prefrontal cortex (DLPFC) are associated with reduced markers of local network activity within PCs and PV basket cells. Functional data indicate impaired activity within VI and PPC during visual tasks in subjects with schizophrenia. Thus, our model predicts that markers of neuronal acfivity are also altered within VI and PPC (Aim 2). Finally, reducfions in pre-synapfic proteins such as synaptophysin and synapsini, that are known to impair glutamatergic bouton funcfion, behavior, and cognifion, have been previously observed in schizophrenia. Our model predicts that reductions in these proteins predominate in intracortical glutamatergic boutons within layer 3 across V1-PPC-DLPFC and are posifively correlated with the magnitude of the underlying somatodendrific abnormalifies within regions in the network (Aim 3). This project serves as an essenfial link between disease-related molecular findings in these same neurons, layers and regions (Project 1) and abnormal information processing in disease (Project 5). This project will constrain the interpretation of how normative functional connectivity (Projects 4 & 5) is altered in disease (Project 5) and will guide predicfions for future studies using markers specific for projections between PPC and DLPFC that may be identified in Project 3. RELEVANCE (See instructions): Individuals with schizophrenia have impairments in attention and working memory, the ability to retain informafion in mind, which are important determinants of day-to-day funcfion. This project will determine if individuals with schizophrenia have impairments in the neuronal structures in three key brain regions that form the circuits responsible for attention and working memory.

该中心的中心假说认为，精神分裂症患者的第三层锥体细胞（PC） 有一种细胞类型自主的病理学，反映在体树突形态的改变， 皮质视觉工作记忆和注意力网络中各个区域的严重程度不同。这些 第3层PC的异常导致局部兴奋性驱动减少，反映在 第3层PC中的代谢活性和相互连接的第3层中的活性依赖性标志物减少 表达小清蛋白（PV）的篮状细胞。这个模型导致了几个新的预测。例如见 第3层PC小体体积和树突棘密度在多个皮质区存在偏差，但 受地区特定因素的调节（目标1）。迄今为止，对初级视觉皮质（VI）的分析有限 已经进行了，后顶叶皮层（PPC）尚未进行检查。我们的初步数据 表明背外侧前额叶皮层（DLPFC）的损伤与以下指标的减少有关： PC和PV篮式电池内的局部网络活动。功能数据表明VI内活动受损， 精神分裂症患者视觉任务期间的PPC。因此，我们的模型预测， 在VI和PPC中，活性也发生了变化（目的2）。最后，突触前蛋白的减少， 突触体素和突触素，已知其损害突触能神经末梢功能、行为， 在精神分裂症中已经观察到。我们的模型预测， 在V1-PPC-DLPFC的第3层内，蛋白质在皮质内突触能终扣中占主导地位， 正相关的程度的潜在体树突异常的区域内， 网络（目标3）。该项目作为这些疾病相关分子发现之间的重要联系， 相同的神经元，层和区域（项目1）和疾病中的异常信息处理（项目5）。 这个项目将限制如何规范的功能连接（项目4和5）的解释是 在疾病中发生改变（项目5），并将使用特定于以下疾病的标记物指导未来研究的预测 PPC和DLPFC之间的预测可能在项目3中确定。 相关性（参见说明）： 精神分裂症患者在注意力和工作记忆方面有障碍， 这些都是日常工作的重要决定因素。该项目将确定如果 患有精神分裂症的个体在三个关键脑区域的神经元结构中有损伤， 形成负责注意力和工作记忆的回路。