Morphological Alterations of Cortical Layer 3 Pyramidal Cells in Schizophrenia

该中心的中心假设假设精神分裂症受试者的第3层锥体细胞(PC) 有一种细胞类型自主的病理，反映在改变的躯体树突状细胞形态中，并且 在大脑皮层视觉工作记忆和注意力网络中，不同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 第三层PC的代谢活性和相互连接的第三层中活性依赖的标记减少 表达小白蛋白(PV)的篮子细胞。这一模型导致了几个新的预测。比方说， 3层PC胞体体积和树突棘密度在多个皮质区域出现偏折，但 受到特定区域因素的制约(目标1)。到目前为止，对初级视皮层的分析有限(VI) 已经进行了检查，但尚未对后顶叶皮质(PPC)进行检查。我们的初步数据 提示背外侧前额叶皮质(DLPFC)的损伤与脑白质损伤标志物的减少有关 PC和PV篮子单元内的本地网络活动。功能数据显示VI和VI中的活动受损 精神分裂症患者在视觉任务中的PPC。因此，我们的模型预测神经元标记物 活性也在VI和PPC内改变(目标2)。最后，突触前蛋白中的还原纤维，如 突触素和突触素，已知会损害谷氨酸能神经元的功能、行为和 认知，此前已在精神分裂症中观察到。我们的模型预测，减少这些 在V1-PPC-DLPFC的第三层皮质内谷氨酸能环中蛋白质占主导地位，并 与基础的躯体树突状细胞异常的大小呈正相关。 网络(目标3)。该项目在这些疾病相关的分子发现之间起到了至关重要的作用 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)。 该项目将限制对如何规范功能连接(项目4和5)的解释 疾病改变(项目5)，并将指导未来研究使用特定于 可能在项目3中确定的PPC和DLPFC之间的预测。 相关性(请参阅说明)： 精神分裂症患者的注意力和工作记忆、保持 头脑中的信息，这是日常运作的重要决定因素。这个项目将决定是否 精神分裂症患者的三个关键脑区的神经元结构受损 形成负责注意力和工作记忆的回路。

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.