Developmental expression profiles of axon guidance signaling and the immune system in the marmoset cortex: potential molecular mechanisms of pruning of dendritic spines during primate synapse formation in late infancy and prepuberty (I)
Developmental expression profiles of axon guidance signaling and the immune system in the marmoset cortex: potential molecular mechanisms of pruning of dendritic spines during primate synapse formation in late infancy and prepuberty (I)
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狨猴皮质中轴突引导信号和免疫系统的发育表达谱：婴儿晚期和青春期前灵长类突触形成过程中树突棘修剪的潜在分子机制（I）
DOI：
10.1016/j.bbrc.2014.01.024
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Ichinohe N*
中科院分区：
文献类型：
--
作者：
Sasaki T;Oga T;Nakagaki K;Sakai K;Sumida K;Hoshino K;Miyawaki I;Saito K;Suto F;Ichinohe N*
灵长类动物的大脑皮层突触数量和相关的树突棘数量在出生后迅速增加。根据大脑区域和物种的不同，突触的数量在成年前达到峰值，在这个峰值之后发生修剪（超调型突触形成）。人类的精神障碍，如自闭症和精神分裂症，被认为是在达到顶峰后过于脆弱或过度修剪的结果。因此，研究过枝型突触形成的分子机制，特别是在修剪阶段是非常重要的。为了研究分子机制，我们以普通狨猴（Callithrix jacchus）为研究对象。对狨猴皮层的腹外侧前额叶、下颞叶和初级视觉皮层进行了微阵列分析，观察到这些区域树突棘数量的变化。以上所有脑区脊柱数在出生后3个月（3个月）达到峰值，然后逐渐减少（如6个月和成人）。在本研究中，我们重点研究了在3 M和6 M年龄之间表现出差异表达的基因以及fold change （FC）大于1.2的差异。选择的基因进行典型途径分析，在本研究中，我们描述轴突引导信号，具有很高的可信度。结果显示，大量基因属于轴突引导信号通路、巨噬细胞/免疫系统、谷氨酸系统等子系统。我们将这些结果的数据和讨论分为2篇论文，这是第一篇论文，涉及轴突引导信号和巨噬细胞/免疫系统。其他系统将在下一篇文章中描述。从3 M到6 M，轴突引导信号中的许多子系统的基因表达发生了变化，使得突触/树突棘数在6 M时减少。因此，轴突引导信号可能导致突触/树突棘数在6 M时减少，这一现象符合灵长类动物的过调型突触形成。小胶质细胞活性（通过量化aif1表达来评估）和调节小胶质细胞分子的基因表达在6 M时下降，就像突触/树突棘数量一样。因此，尽管小胶质细胞的活性被认为与突触/树突棘的吞噬有关，但单独的小胶质细胞活性不能解释在修剪阶段如何加速修剪。另一方面，标记突触/树突棘作为小胶质细胞吞噬靶标的分子（如补体成分）在6 M时表达增加，表明这些标记蛋白可能参与了修剪阶段的加速修剪。
The synapse number and the related dendritic spine number in the cerebral cortex of primates shows a rapid increase after birth. Depending on the brain region and species, the number of synapses reaches a peak before adulthood, and pruning takes place after this peak (overshoot-typesynaptic formation). Human mental disorders, such as autism and schizophrenia, are hypothesized to be a result of either too weak or excessive pruning after the peak is reached. Thus, it is important to study the molecular mechanisms underlyingovershoot-typesynaptic formation, particularly the pruning phase.To examine the molecular mechanisms, we used common marmosets (Callithrix jacchus). Microarray analysis of the marmoset cortex was performed in the ventrolateral prefrontal, inferior temporal, and primary visual cortices, where changes in the number of dendritic spines have been observed. The spine number of all the brain regions above showed a peak at 3 months (3 M) after birth and gradually decreased (e.g., at 6 M and in adults). In this study, we focused on genes that showed differential expression between ages of 3 M and 6 M and on the differences whose fold change (FC) was greater than 1.2. The selected genes were subjected to canonical pathway analysis, and in this study, we describe axon guidance signaling, which had high plausibility. The results showed a large number of genes belonging to subsystems within the axon guidance signaling pathway, macrophages/immune system, glutamate system, and others. We divided the data and discussion of these results into 2 papers, and this is the first paper, which deals with the axon guidance signaling and macrophage/immune system. Other systems will be described in the next paper. Many components of subsystems within the axon guidance signaling underwent changes in gene expression from 3 M to 6 M so that the synapse/dendritic spine number would decrease at 6 M. Thus, axon guidance signaling probably contributes to the decrease in synapse/dendritic spine number at 6 M, the phenomenon that fits theovershoot-typesynaptic formation in primates.Microglial activity (evaluated by quantifyingAIF1expression) and gene expression of molecules that modulate microglia, decreased at 6 M, just like the synapse/dendritic spine number. Thus, although microglial activity is believed to be related to phagocytosis of synapses/dendritic spines, microglial activity alone cannot explain how pruning was accelerated in the pruning phase. On the other hand, expression of molecules that tag synapses/dendritic spines as a target of phagocytosis by microglia (e.g., complement components) increased at 6 M, suggesting that these tagging proteins may be involved in the acceleration of pruning during the pruning phase.