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: 9355827
• 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/9355827
• 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.

该中心的中心假设认为，精神分裂症患者的第 3 层锥体细胞 (PC) 具有细胞类型自主病理学，反映在体细胞树突形态的改变中 皮质视觉工作记忆和注意力网络中不同区域的严重程度有所不同。这些 第 3 层 PC 的异常导致局部兴奋性驱动力降低，反映在 第 3 层 PC 中的代谢活动和相互连接的第 3 层中的活动依赖性标记减少 表达小清蛋白（PV）的篮子细胞。这个模型导致了一些新颖的预测。例如，那个 第 3 层 PC 体体积和树突棘密度的缺陷存在于多个皮质区域，但是 由区域特定因素调节（目标 1）。迄今为止，仅对初级视觉皮层 (VI) 进行了有限的分析 已进行，但尚未检查后顶叶皮质（PPC）。我们的初步数据 表明背外侧前额皮质 (DLPFC) 的损伤与 PC 和 PV 篮式电池内的本地网络活动。功能数据表明 VI 内的活动受损， 精神分裂症受试者视觉任务期间的 PPC。因此，我们的模型预测神经元标记 VI 和 PPC 中的活动也会发生变化（目标 2）。最后，突触前蛋白的减少，例如 突触素和突触素，已知会损害谷氨酸布顿功能、行为和 认知能力，此前已在精神分裂症中观察到。我们的模型预测这些减少 蛋白质在 V1-PPC-DLPFC 第 3 层内的皮质内谷氨酸能开关中占主导地位，并且是 与区域内潜在体树突异常的程度呈正相关 网络（目标 3）。该项目充当了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）以及疾病中的异常信息处理（项目 5）。 该项目将限制对规范功能连接（项目 4 和 5）的解释 疾病发生改变（项目 5），并将指导使用特定标记物进行未来研究的预测 PPC 和 DLPFC 之间的预测可以在项目 3 中确定。 相关性（参见说明）： 精神分裂症患者的注意力和工作记忆、保留信息的能力都会受到损害。 牢记信息，这是日常功能的重要决定因素。该项目将确定是否 精神分裂症患者三个关键大脑区域的神经元结构受损 形成负责注意力和工作记忆的电路。