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

我们对严重精神疾病（包括精神分裂症）的理解和治疗落后于其他主要医学疾病，至少有两个重要原因，包括1）人类大脑无与伦比的复杂性和我们对精神疾病病理生理学的初步理解，以及2）仍然有限的翻译工具可用于测试和验证人体内的假定机制。 在许多人海陵为我们对精神分裂症的神经生物学理解的突破中，Sekar及其同事最近暗示了一种“免疫系统蛋白”，补体成分4（C4），在其病因学中。在主要组织相容性复合体中一个戏剧性的，尽管无法解释的，全基因组显著关联的指导下，他们确定了1）C4基因的复杂结构变异，与精神分裂症风险和脑C4 A 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C4 A RNA的升高，以及3）使用小鼠遗传模型，一种有前景的病理生理机制（即，异常突触修剪），由此升高的C4 A水平导致突触完整性被破坏。然而，到目前为止，这种机制的相关性还没有建立在活的人脑上。 我们的小组已经开发出一种新的放射性示踪剂，11 C-UCB-J，现在可以用正电子发射断层扫描（PET）成像活体人脑中的突触密度。 目前的探索性/发展性（R21）应用将应用这种突破性的方法来探索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，目前的研究将首次在活体人脑中为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原因的机械理解的关键突破之上。

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.