Neural-immune mechanisms and synaptic connectivity in psychiatric illness

神经精神障碍背后的病理生理过程一直未知；因此， 这些疾病缺乏具有新作用机制的创新医学疗法。我们最近 确定人类基因组对精神分裂症风险的最大群体水平影响的等位基因 -补体C4a和C4b基因的一系列结构等位基因，每一个似乎都影响 精神分裂症的风险与它在大脑中产生的C4a表达量成比例。我们还发现， C4在出生后活动依赖突触消除的小鼠模型中塑造突触细化。这些 这些发现可能有助于解释精神分裂症的已知特征，包括关键区域突触数量的减少 皮质区域和青春期发病年龄与发育计时波相对应 这些区域的突触修剪。 我们为Conte中心设想的工作的目标是发展我们对神经免疫的理解 相互作用和突触，同时产生新的科学资源，可用于评估当前 以及未来关于精神分裂症相关基因、神经免疫相互作用和关键期的假设 用来提炼突触。我们提出的工作源于科学家与 在基因组学、免疫学和神经科学方面的专业知识。我们的目标是通过以下方式完成我们中心的使命 科学项目和核心。项目1将试图了解中枢神经系统细胞如何调节 当基因表达经过其回路成熟的关键时期时，补充和重新编程基因表达。 项目2将创造携带人类C4基因和等位基因的小鼠；研究人类C4等位基因多样性 表达水平影响小胶质细胞介导的突触修剪和其他过程。项目3将揭示 补体-级联失调的功能后果--过度修剪和不足修剪-ON回路 功能和行为。一个计算和统计分析核心将对这三个领域的研究作出贡献 促进全基因组表达数据和基因组序列数据分析的项目。一个 行政核心将协调两周一次的实验室会议和对外活动，包括每年一次的 神经科学、免疫学和基因组学相结合的新兴研究专题讨论会。 我们希望推进对精神分裂症的分子理解的探索，同时推进 了解大脑发育、基因和环境对大脑的交互影响以及 行为，以及可能适用于 患有其他精神疾病。

The pathophysiological processes underlying neuropsychiatric disorders have been unknown; as a result, these disorders have lacked innovative medical therapies with new mechanisms of action. We recently identified the alleles underlying the human genome's largest population-level influence on risk of schizophrenia – a series of structural alleles of the complement C4A and C4B genes, each of which appears to affect schizophrenia risk in proportion to the amount of C4A expression it generates in the brain. We also found that C4 shapes synaptic refinement in a mouse model of postnatal activity-dependent synapse elimination. These findings may help explain known features of schizophrenia, including reduced numbers of synapses in key cortical regions and an adolescent age of onset that corresponds with developmentally timed waves of synaptic pruning in these regions. The goal of the work we envision for a Conte Center is to develop our understanding of neural-immune interactions and synapses while also generating novel scientific resources that can be used to evaluate current and future hypotheses about schizophrenia-implicated genes, neural-immune interactions, and critical periods for synaptic refinement. Our proposed work arises from close, successful collaboration of scientists with expertise in genomics, immunology, and neuroscience. We aim to accomplish our Center's missions through scientific projects and cores. Project 1 will seek to understand how CNS cells regulate the expression of complement and reprogram gene expression as they traverse critical periods in the maturation of their circuits. Project 2 will create mice that carry human C4 genes and alleles; examining how human C4 allelic diversity and expression levels affect microglia-mediated synaptic pruning and other processes. Project 3 will reveal the functional consequences of complement-cascade dysregulation – both over- and under-pruning – on circuit function and behavior. A Computational and Statistical Analysis Core will contribute to research in all three projects by facilitating analyses of genome-wide expression data and genome sequence data. An administrative core will coordinate biweekly lab meetings and outward-facing activities, including an annual symposium on emerging research at the interface of neuroscience, immunology and genomics. We hope to advance the search for molecular understanding of schizophrenia while advancing the understanding of brain development, the interacting influences of genes and environment on brain and behavior, and possibly general principles that could be applicable to the mechanisms and pathways that go awry in other mental illnesses.