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受试者的3层锥体细胞（PC） 具有细胞型自主病理学，在改变的躯体形态中被修改，并且 皮质视觉工作记忆和注意力网络中各个区域的严重程度有所不同。这些 第3层PC的异常导致局部减少兴奋性驱动，并在减少 第3层PC中的代谢活性以及相互连接3层的活动依赖性标记降低 白蛋白（PV）表达篮子细胞。该模型导致了几种新颖的预测。例如，那 在Mulfiple皮质区域中存在第3层PC的som体积和树突状脊柱密度的缩放，但是 通过区域特异性因素进行调节（AIM 1）。迄今为止，仅对主要视觉皮层（VI）的分析有限 已经进行了，并且尚未检查后顶叶皮层（PPC）。我们的初步数据 表明背外侧前额叶皮层（DLPFC）的损伤与标记的标记相关 PC和PV篮细胞中的局部网络活动。功能数据表明VI和 精神分裂症受试者的视觉任务期间的PPC。因此，我们的模型预测神经元的标记 在VI和PPC内也有所改变（AIM 2）。最后，在核对前蛋白（例如 突触素和突触 认知先前在精神分裂症中已经观察到。我们的模型预测这些减少 蛋白质在第3层跨V1-PPC-DLPFC中的物质内谷氨酸能式胸子中占主导地位，并且 与潜在的种子义异常相关的区域内的大小 网络（目标3）。该项目是这些项目之间与疾病相关的分子发现之间的典型联系 相同的神经元，层和区域（项目1）和疾病中的信息处理异常（项目5）。 该项目将限制对规范功能连接的解释（项目4和5） 疾病的改变（项目5），并将使用特定的标记来指导未来研究的预测 PPC和DLPFC之间的预测可以在项目3中确定。 相关性（请参阅说明）： 精神分裂症患者的注意力和工作记忆有障碍，保留的能力 考虑到Informafion，这是日常功能的重要决定因素。这个项目将确定是否 精神分裂症的个体在三个关键大脑区域的神经元结构中有损害 形成负责注意和工作记忆的电路。