Trajectory of change in brain complement factors from neonatal to young adult humans
Trajectory of change in brain complement factors from neonatal to young adult humans
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DOI：
10.1111/jnc.15241
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发表时间：
2020-12-15
影响因子：
4.7
通讯作者：
Weickert, Cynthia Shannon
中科院分区：
文献类型：
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作者：
Sager, Rachel E. H.;Walker, Adam K.;Weickert, Cynthia Shannon
免疫系统成分还调节神经发育中突触的形成和细化。补体途径与细胞裂解和吞噬作用相关，与突触消除有关。异常的青少年突触修剪可能是精神分裂症发病的基础；因此，人类发育过程中皮质补体活动的变化引起了人们的重大兴趣。补体通过增加 C4 拷贝数变异与精神分裂症存在遗传关联，但补体表达在人脑中的发育轨迹尚未确定。随着啮齿类动物突触活跃期间补体的增加，我们假设补体表达会在人类出生后发育期间增加，特别是在青春期。使用人类死后前额叶皮层，我们观察到补体激活剂（C1QB 和 C3）转录物在早期神经发育中达到峰值，在幼儿中最高，在青少年中下降（所有 ANCOVA 均在 F = 2.41 -3.325 之间，p = .01-0.05）。我们发现 C4 蛋白在 1-5 岁时较高（H = 16.378，p = .012），而 C3 蛋白水平随着年龄的增长而没有变化。小胶质细胞补体受体亚基 CD11b 的 mRNA 在生命早期增加，并在幼儿大脑中达到峰值（ANCOVA：pH，F = 4.186，p = .003）。补体抑制剂（CD46 和 CD55）在学龄期增加，但未能像补体激活剂一样减少（均为 ANCOVA，F > 4.4，p < .01）。这些数据表明，人类前额皮质中的补体激活发生在 1 到 5 年之间。我们没有发现青春期补体因子诱导的证据，而是发现成熟时补体抑制剂 mRNA 水平增加或持续。这些典型补体模式的失调可能会使大脑容易出现神经发育障碍，例如自闭症或精神分裂症。
Immune system components also regulate synapse formation and refinement in neurodevelopment. The complement pathway, associated with cell lysis and phagocytosis, is implicated in synaptic elimination. Aberrant adolescent synaptic pruning may underpin schizophrenia onset; thus, changes in cortical complement activity during human development are of major interest. Complement is genetically linked to schizophrenia via increased C4 copy number variants, but the developmental trajectory of complement expression in the human brain is undetermined. As complement increases during periods of active synaptic engulfment in rodents, we hypothesized that complement expression would increase during postnatal development in humans, particularly during adolescence. Using human postmortem prefrontal cortex, we observed that complement activator (C1QB and C3) transcripts peaked in early neurodevelopment, and were highest in toddlers, declining in teenagers (all ANCOVAs between F = 2.41 -3.325, p = .01-0.05). We found that C4 protein was higher at 1-5 years (H = 16.378, p = .012), whereas C3 protein levels were unchanged with age. The microglial complement receptor subunit CD11b increased in mRNA early in life and peaked in the toddler brain (ANCOVA: pH, F = 4.186, p = .003). Complement inhibitors (CD46 and CD55) increased at school age, but failed to decrease like complement activators (both ANCOVAs, F > 4.4, p < .01). These data suggest the activation of complement in the human prefrontal cortex occurs between 1 and 5 years. We did not find evidence of induction of complement factors during adolescence and instead found increased or sustained levels of complement inhibitor mRNA at maturation. Dysregulation of these typical patterns of complement may predispose the brain to neurodevelopmental disorders such as autism or schizophrenia.