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

摘要：多条证据表明，增加突触修剪具有重要的病理生理学意义。 治疗精神分裂症(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证明补体(C4)基因 重复序列与SZ风险显著相关，尤其是C4a长型(C4AL)。C4蛋白在细胞中的表达 精神分裂症患者的大脑与C4AL重复次数成比例增加。一只老鼠 在啮齿动物模型中，C4的类似物与突触修剪的增加有关。我们建议开发两个 关于遗传因素与突触修剪相关的独立证据。我们的活体方法 将纵向检查使用超高场结构MRI和 7特斯拉基线、6个月和1年的磷磁共振波谱(31P MRS) 青少年早发性系统性红斑狼疮(EOS)与健康对照(HC)及其与认知功能的关系 (目标1)、C4重复和通过多基因风险评分(PGRs)衡量的全球遗传责任(目标2)。这个 青少年EOS和HC纵向检查的理论基础得到更突出的突触的支持 青春期的修剪。7特斯拉的超高场结构MRI和31P MRS提供卓越的分辨率 以及对代谢物定量的更高的敏感性。~(31)P-MRS测定膜磷脂代谢物 (MPL)横跨整个大脑。MPL前体指数降低减少了神经纤维的形成，而 MPL分解产物的增加反映了神经纤维的收缩。由于突触嵌入在神经纤维束中 膜扩张的主要部分由突触、树突和树突贡献， MPL代谢物水平被建议提供更特异和更敏感的神经抑制指标 灰色物质度量。另外一个衡量神经膜收缩的指标是皮质厚度。 测量。PGRS是一种更准确地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测树突棘的密度和形态与C4蛋白表达的关系 -在分化人类过程中，自然界和诱导C4蛋白的过度和低表达 诱导多能干细胞(HiPSC)衍生的神经元器质(目标3)。有机物体是三维的 神经元培养显示出更精细的显微解剖特征，能够概括一些特定的 与二维培养相比，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 31P MRS和皮质厚度发现可能代表突触修剪。只提出一条证据 留下了关于遗传因素与神经束修剪之间的关联的悬而未决的问题。审查一项重要的 与遗传风险有关的病理生理过程，即突触修剪，可能有助于识别关键的 最终开发治疗SZ的新方法的途径和特定的分子靶点。

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.