Imaging Complement Component 4 Gene Effects on Human Synaptic Density in Vivo Using 11C-UCB-J PET

我们对包括精神分裂症在内的严重精神疾病的理解和治疗落后于其他重大医学疾病，至少有两个重要原因，包括1)人脑的无与伦比的复杂性，以及我们对精神疾病病理生理学的唯一初步了解，以及2)可用于测试和验证人体体内假定机制的翻译工具仍然有限。 在许多人欢呼为我们对精神分裂症的神经生物学理解的突破，Sekar和他的同事最近在其病因学中涉及一种“免疫系统蛋白”--补体成分4(C4)。在主要组织相容性复合体中一个戏剧性的、尽管原因不明的全基因组显著关联的指导下，他们发现了1)C4基因的复杂结构变异，与精神分裂症风险和脑C4a RNA表达的平行、剂量依赖性增加有关；2)精神分裂症患者死后脑组织中C4a RNA的升高；以及3)使用小鼠遗传模型，一种有希望的病理生理学机制(即异常突触修剪)，C4a水平升高导致突触完整性破坏。然而，到目前为止，这一机制对活着的人脑的相关性尚未确定。 我们团队开发了一种新的放射性示踪剂11C-UCB-J，现在可以用正电子发射断层扫描(PET)对活体人脑中的突触密度进行成像。目前的探索性/发展性(R21)应用将应用这一突破性方法学来探索C4的遗传变异是否与人类突触密度的改变有关。 如果得到证实，目前的研究将在活着的人脑中首次为C4介导的精神分裂症风险的异常突触修剪假说提供令人信服的支持。因此，它将验证并建立在我们对精神分裂症及其病因的机械论理解的关键突破的基础上。

Our understanding and treatment of serious mental illness, including schizophrenia, has lagged that for other major medical illnesses for at least two important reasons, including 1) the unparalleled complexity of the human brain and our only nascent understanding of psychiatric disease pathophysiology, and 2) the still limited translational tools available for testing and validating putative mechanisms in humans in vivo. In what many are hailing as a breakthrough in our neurobiological understanding of schizophrenia, Sekar and colleagues recently implicated an “immune system protein,” complement component 4 (C4), in its etiology. Guided by a dramatic, albeit unexplained, genome-wide significant association in the major histocompatibility complex, they identified 1) complex structural variation in the C4 gene that was associated with parallel, dose- dependent increases in both schizophrenia risk and brain C4A RNA expression, 2) elevations in C4A RNA in post- mortem brain tissue from schizophrenia patients, and 3) using a mouse genetic model, a promising pathophysiological mechanism (i.e., aberrant synaptic pruning), whereby elevated C4A levels lead to disrupted synaptic integrity. To date, however, the relevance of this mechanism has yet to be established for the living human brain. Our group has developed a novel radiotracer, 11C-UCB-J, which now enables the imaging of synaptic density in the living human brain with positron-emission tomography (PET). The current exploratory/developmental (R21) application will apply this breakthrough methodology to explore whether genetic variation in C4 is associated with altered synaptic density in humans. If confirmed, the current study would provide compelling support for the aberrant synaptic pruning hypothesis of C4-mediated risk for schizophrenia, for the first time in the living human brain. As such, it would validate and build-upon a crucial breakthrough in our mechanistic understanding of schizophrenia and its causes.