Immune molecules and synaptic connectivity in maternal immune activation offspring and schizophrenia

摘要：项目1 尽管精神分裂症的流行和巨大的社会成本，目前的治疗精神分裂症（SZ）， 对所有人都有效，但对治疗认知障碍和阴性症状几乎没有作用。因此，有一个 迫切需要确定新的分子途径，以开发新的化合物和工具， SZ的诊断和治疗我们的中心专注于测试免疫分子可能 形成了这样的目标路径。免疫基因位于主要组织相容性复合体（MHC）内 在最近的全基因组关联研究中， 疾病的最佳环境风险因素。小鼠和非人类的发展 灵长类动物（NHP）母体感染模型也加强了母体免疫与 激活（MIA）和SZ，因为这些模型概括了许多SZ相关的表型， 神经生物学和行为水平。尽管我们的工作正在为 尽管它们在模拟SZ的核心表型方面的功效，但对MIA如何改变脑发育知之甚少。 出生导致后代出现SZ相关表型。该项目将确定MIA如何以及何时改变神经系统 出生后发育过程中的连接，以及这些变化是否取决于MIA诱导的变化， 后代大脑中的MHCI水平。为实现这些目标，本项目将开展三项具体工作： 目的是确定：1）MIA是否改变了小鼠和NHP后代大脑中的突触密度和类型 模型在整个出生后的发展和死后的脑组织与SZ个人使用 包括称为阵列断层扫描的创新技术的方法; 2）如果MIA改变小胶质细胞激活 和免疫分子水平，包括MHCI，在两种动物模型的后代大脑中， 发展以及死后脑组织与SZ的个人; 3）如果在免疫变化， 来自小鼠模型的后代大脑中的分子通过评估是否 将神经元MHCI水平恢复到正常可防止MIA诱导的突触连接性变化， 在后代中的SZ样行为。通过实现这些目标，项目1将直接解决中央 中心的假设以机械的方式。此外，跨尺度进行这些实验将 识别MIA诱导的突触连接变化与人类疾病相关， NHP模型中的守恒。该项目的成果对其他项目的成功至关重要， 该中心提供了转录网络变化的表型读出（项目2）， 结构和功能连接（项目3），以及关于小胶质细胞是否 激活介导MIA模型和SZ患者中神经炎症的变化（项目4）。如果 如果成功，该项目的结果将确定开发更有效诊断工具的新目标， SZ和其他精神疾病的治疗与神经免疫的基础。

SUMMARY: PROJECT 1 Despite its prevalence and enormous cost to society, current treatments for schizophrenia (SZ) are not effective in all individuals and do little to treat the disabling cognitive and negative symptoms. Thus, there is a pressing need to identify new molecular pathways to target in developing new compounds and tools for earlier diagnosis and treatment of SZ. Our Center is focused on testing the hypothesis that immune molecules may constitute such a target pathway. Immune genes located within the major histocompatibility complex (MHC) have been reliability identified in recent genome-wide association studies, while maternal infections are among the best-established environmental risk factors for the illness. The development of mouse and non-human primate (NHP) models of maternal infection has also strengthened the link between maternal immune activation (MIA) and SZ because these models recapitulate many SZ related phenotypes at both the neurobiological and behavioral levels. Although our work is providing increasingly compelling validation for their efficacy in mimicking core phenotypes of SZ, little is known about how MIA alters brain development after birth to cause SZ-related phenotypes in offspring. This project will determine how and when MIA alters neural connectivity during postnatal development and whether those changes depend on MIA-induced changes in MHCI levels in the brains of offspring. To accomplish these objectives, this project will undertake three specific aims to determine: 1) if MIA alters synapse density and type in the brains of offspring of the mouse and NHP models throughout postnatal development and in postmortem brain tissue from individuals with SZ using approaches that include an innovative technique called array tomography; 2) if MIA alters microglial activation and levels of immune molecules, including MHCI, in the brains of offspring in both animal models throughout development as well as in postmortem brain tissue from individuals with SZ; 3) if changes in immune molecules in the brains of offspring from the mouse model mediate the effects of MIA by assessing whether restoring levels of neuronal MHCI back to normal prevents MIA-induced changes in synaptic connectivity and SZ-like behaviors in offspring. By accomplishing these aims, Project 1 will directly address the central hypothesis of the Center in a mechanistic manner. Moreover, performing these experiments across scales will identify which MIA-induced changes in synaptic connectivity are relevant to human disease through their conservation in the NHP model. Results from this project are essential to the success of the other projects in the Center in providing a phenotypic read-out for changes in transcriptional networks (Project 2) and in structural and functional connectivity (Project 3), as well as critical information about whether microglial activation mediates changes in neural inflammation (Project 4) in MIA models and humans with SZ. If successful, results from this project will identify novel targets for developing more effective diagnostic tools and therapies for SZ and other psychiatric illnesses with a neural-immune basis.