Project-004

精神分裂症的病理生理学尚不清楚，导致缺乏创新的研究 具有新颖作用机制的疗法。孔特神经免疫研究中心 我们的发现是最重要的精神分裂症背后的生物学基础 常见的遗传风险变异涉及突触修剪的神经免疫机制。我们有 发现补体成分 C4 基因的风险变异与增加 C4A 在大脑和 CSF 中的表达，以及人类 C4A 在小鼠模型中的过度表达 导致过度的突触修剪和社会行为缺陷。我们进一步表明 在精神分裂症风险位点 CD47 和 CSMD1 编码的其他神经免疫分子， 影响突触修剪和补体活动。最后，精神分裂症在人群中并不常见。 青春期晚期/成年早期发病的神经发育障碍，以及童年时期的逆境 精神分裂症的主要非遗传危险因素；然而青少年的生物学基础 精神脆弱性是完全未知的。我们已经确定了电路的关键时期 我们提出的小鼠额叶皮层的细化可用于更好地理解 青少年大脑发育对精神危险因素的独特脆弱性。 该中心未来五年的目标是加深对 C4 介导的关注 突触修剪作为一种病理生理机制，并扩大我们的研究范围 更全面地了解神经免疫通路、其上游调节因子、细胞 效应器及其下游电路级和行为影响。项目1将调查 星形胶质细胞（大脑中 C4 的主要来源）通过操纵精神分裂症风险基因的作用 在这些细胞中并分析对突触形成和功能的影响。项目2将在空间上 绘制大脑对 C4 过度表达的转录反应，并测试治疗效果 假设抑制 C4 活性可以挽救过度修剪和相关行为 表型。项目 3 将检查青少年关键期的回路特异性， 基因与环境风险因素相互作用的影响以及大脑边界的作用。项目 4 将探索基底神经节和额叶皮层之间的电路级相互作用 青少年发展、精神风险因素和风险/回报决策。我们还将 为扩大非人类精神风险的神经免疫研究奠定基础 灵长类动物模型，狨猴。最后，我们的行政核心将促进跨学科 合作利用四个实验室的全方位专业知识，并向外协调 面临的活动包括年度研究研讨会。

The pathophysiology of schizophrenia has been unknown, resulting in a lack of innovative therapeutics with novel mechanisms of action. The Conte Center for Neuroimmune Studies was created to build on our discovery that the biology underlying the most significant schizophrenia common genetic risk variants involves neuroimmune mechanisms of synaptic pruning. We have found that risk variants of the complement component C4 genes are correlated with increased C4A expression in the brain and CSF, and that overexpression of human C4A in a mouse model results in excess synaptic pruning and social behavioral deficits. We have further shown that additional neuroimmune molecules encoded at schizophrenia risk loci, CD47 and CSMD1, influence synaptic pruning and complement activity. Lastly, schizophrenia is unusual among neurodevelopmental disorders in its late-adolescent/early-adult onset, and childhood adversity is a major non-genetic risk factor for schizophrenia; yet the biological underpinnings of adolescent psychiatric vulnerability are wholly unknown. We have identified a critical period of circuit refinement in the mouse frontal cortex that we propose can be exploited to better understand the unique vulnerability of adolescent brain development to psychiatric risk factors. The goals of the Center in our next five years are to both deepen the focus on C4-mediated synaptic pruning as a pathophysiological mechanism, and expand the scope of our investigations to create a fuller picture of neuroimmune pathways, their upstream regulators, their cellular effectors, and their downstream circuit-level and behavioral impacts. Project 1 will investigate the role of astrocytes, the main source of C4 in the brain, by manipulating schizophrenia risk genes in these cells and assaying the impacts on synapse formation and function. Project 2 will spatially map the brain’s transcriptional response to C4 overexpression, and test the therapeutic hypothesis that inhibition of C4 activity may rescue over-pruning and associated behavioral phenotypes. Project 3 will examine the circuit specificity of the adolescent critical period, the impacts of gene-by-environment risk factor interactions, and the roles of the brain borders. Project 4 will explore circuit-level interactions between the basal ganglia and frontal cortex in the context of adolescent development, psychiatric risk factors, and risk/reward decision-making. We will also lay the groundwork for expanding neuroimmune studies of psychiatric risk to a non-human primate model, the marmoset. Finally, our Administrative Core will facilitate interdisciplinary collaboration that exploits the full range of expertise across the four labs, and coordinate outward- facing activities including the annual research symposium.