Molecular Alterations of Cortical Layer 3 Pyramidal Cells in Schizophrenia

项目1(P1)在特定细胞类型水平上为中央的以下方面提供了分子测试 假设：1)精神分裂症的核心皮质病理影响第三层锥体细胞，2)影响 这种基因表达的病理变化受到不同皮质区域因素的影响。第3层 将使用激光显微解剖在死后样本中收集锥体细胞 精神分裂症或分裂情感障碍与健康对照(目标1)。区域内分析 将介绍精神分裂症第三层锥体细胞的细胞自主病理。跨地区 分析将表征对照对象的分子区域特异性，以及它们如何影响 精神分裂症第三层锥体细胞的病理学研究。次要目标是洞察潜力 分子靶点是恢复视觉工作记忆和注意力网络的功能平衡。 因此，由于第3层锥体细胞的改变被预测会在 含有小白蛋白(PV)的GABA神经元，将在PV中进行类似的分析 神经元(目标2)。为了提供关于协调局部电路改变的全面分子观点， 基因表达(信使核糖核酸)和基因调控微核糖核酸(MiRNA)将并行研究(AIMS 1-2)和涉及健康控制和病理条件的生物模块将通过以下方式确定 不同细胞类型、区域和队列之间协调表达的变化(目标3)。PI的结果将 通知所有其他中心项目关于中心假设的分子和细胞基础 地区差异缓和了精神分裂症患者第三层PC改变的严重程度。PI还将提供 P2中蛋白质标记研究的分子线索，以及第3层PC中 P3的电生理特性。联合项目1-3将提供分子、细胞和电路 猴子功能连通性研究的基础(P4)，以及健康对照和 精神分裂症受试者(P5)。

Project 1 (P1) provides molecular tests at the cell type-specific level for the following aspects of the Central Hypothesis: 1) a core cortical pathology in schizophrenia affects layer 3 pyramidal cells, and 2) the impact of this pathology on gene expression is moderated by factors that differ across cortical regions. Layer 3 pyramidal cells will be collected using laser microdissection in postmortem samples from subjects with schizophrenia or schizoaffective disorder and healthy comparison subjects (Aim 1). Within-region analyses will inform on the cell autonomous pathology of layer 3 pyramidal cells in schizophrenia. Across-region analyses will characterize molecular regional specificities in control subjects and how they impact the pathology of layer 3 pyramidal cells in schizophrenia. A secondary goal is to gain insight into potential molecular targets to restore functional balance along the visual working memory and attention network. Accordingly, since layer 3 pyramidal cell alterations are predicted to induce transcriptional responses in the parvalbumin (PV)-containing GABA neurons that they innervate, similar analyses will be performed in PV neurons (Aim 2). To provide a comprehensive molecular perspective on coordinated local circuit alterations, expression of genes (mRNA) and gene regulatory micro-RNAs (miRNA) will be investigated in parallel (Aims 1-2) and biological modules implicated in healthy control and pathological conditions will be identified by changes in coordinated expression across cell types, regions and cohorts (Aim 3). Results from PI will inform all other Center projects on the molecular and cellular bases in regards to the Central Hypothesis that regional differences moderate the serverity of layer 3 PC alterations in schizophrenia. PI will also provide molecular leads for protein marker studies in P2, and for layer 3 PC regional differences in electrophysiological properties in P3. Together Projects 1-3 will provide the molecular, cellular and circuitry bases for the functional connectivity studies in monkey (P4), and in imaging studies of healthy controls and subjects with schizophrenia (P5).