Synaptic Pruning and Complement Gene in Schizophrenia: Imaging & Cellular Studies

翻译后摘要：多线的证据表明，增加突触修剪是病理生理意义 用于精神分裂症（SZ）。新出现的证据表明，遗传因素与突触增加有关。 在深圳修剪。最近的全基因组关联研究令人信服地表明，补体（C4）基因 重复与SZ风险显著相关，特别是C4A长型（C4AL）。C4蛋白表达 精神分裂症患者的脑中C4AL重复的数量成比例地增加。鼠标 在啮齿动物模型中，C4类似物与突触修剪增加相关。我们建议发展两个 关于遗传因素与突触修剪相关性的独立证据。我们的体内方法 将纵向检查使用超高场结构MRI获得的突触修剪措施， 在基线、6个月和1年时， 早发性SZ青少年（EOS）和健康对照（HC），及其与认知能力的关系 (Aim 1），C4重复序列和通过多基因风险评分（PGRS）测量的总体遗传易感性（目的2）。的 青少年EOS和HC纵向检查的基本原理得到了更突出的突触 在青春期修剪。超高场结构MRI和7 T的31 P MRS提供了优越的上级分辨率 和更高的代谢物定量灵敏度。31P MRS测量膜磷脂的代谢产物 (MPL)整个大脑。MPL前体指数降低可减少神经元的形成， 增加的MPL分解产物反映神经元收缩。因为突触是嵌在神经细胞中的 而膜扩张的主要部分是由突触、树突分支和树突棘贡献的， MPL代谢物水平被提议提供比MPL代谢物水平更特异和更灵敏的神经递质测量。 灰质测量另一个衡量神经收缩的指标是通过皮质厚度 测量. PGRS是一种更准确的衡量全基因组变异所带来的总体遗传风险的方法。 我们的体外方法将检查树突棘密度和形态与C4蛋白表达的关系。 - 在分化的人类中， 诱导多能干细胞（hiPSC）衍生的神经元类器官（Aim 3）。类器官是三维的 神经元培养物显示出更精细的显微解剖特征，能够重现一些特定的 与二维文化相比，大脑的功能。除了提供独立的证据， 突触密度与C4蛋白表达相关，hiPSC模型为突触密度与C4蛋白表达相关提供了一些确凿的证据。 31P MRS和皮质厚度发现可能代表突触修剪。只提出了一条证据 留下了关于遗传因素与神经系统修剪之间联系的开放性问题。检查一个重要的 病理生理过程，即突触修剪，与遗传风险的关系可能有助于确定关键的 途径和特定的分子靶点，最终开发新的治疗SZ。

Abstract: Multiple lines of evidence suggest that increased synaptic pruning is pathophysiologically significant for schizophrenia (SZ). Emerging evidence suggests that genetic factors are associated with increased synaptic pruning in SZ. Recent genome-wide association studies convincingly demonstrated that Complement (C4) gene repeats were significantly associated with SZ risk, specifically C4A long form (C4AL). C4 protein expression in the brains of schizophrenia patients was increased proportionate to the number of C4AL repeats. A mouse analog of C4 was associated with increased synaptic pruning in a rodent model. We propose to develop two independent lines of evidence on the association of genetic factors with synaptic pruning. Our in vivo approach will longitudinally examine measures of synaptic pruning obtained using ultra-high field structural MRI and phosphorus magnetic resonance spectroscopy (31P MRS) at 7 Tesla at baseline, 6-months and 1-year among adolescents with early onset SZ (EOS) and healthy controls (HC), and its association with cognitive performance (Aim 1), C4 repeats and global genetic liability measured through polygenic risk score (PGRS) (Aim 2). The rationale for longitudinal examination of adolescent EOS and HC is supported by more prominent synaptic pruning during adolescence. Ultra-high field structural MRI and 31P MRS at 7 Tesla provides superior resolution and greater sensitivity for metabolite quantification. 31P MRS measures metabolites of membrane phospholipids (MPL) across the entire brain. Decreased MPL precursors index decreased neuropil formation whereas increased MPL breakdown products reflect neuropil contraction. Since synapses are embedded in the neuropil and major part of membrane expansion is contributed by synapses, dendritic branches and dendritic spines, MPL metabolite levels are proposed to provide more specific and sensitive measure of neuropil compared to gray matter metrics. An additional measure to index neuropil contraction is through cortical thickness measurements. PGRS is a more accurate measure of overall genetic risk conferred by genomewide variations. Our in vitro approach will examine dendritic spine density and morphology in relation to expression of C4 proteins - both naturalistically and with induction of over- and under- expression of C4 proteins in differentiating human induced pluripotent stem cell (hiPSC)-derived neuronal organoids (Aim 3). Organoids are 3-dimensional neuronal cultures that show more refined microanatomic feature capable of recapitulating some specific functions of the brain compared to 2-dimensional cultures. In addition to providing independent evidence of synaptic density related to C4 protein expression, hiPSC model provides some corroborative evidence for the 31P MRS and cortical thickness findings that may represent synaptic pruning. Proposing only one line of evidence leaves open questions about the association of genetic factors with neuropil pruning. Examining an important pathophysiological process, namely synaptic pruning, in relation to genetic risk may help identify critical pathways and specific molecular targets for eventual development of novel treatments for SZ.