小胶质细胞在神经发育过程中异常激活和增殖可诱发神经精神疾病，然而其中的调控机制尚知之甚少。我们发现自闭症高危基因chd8在小胶质细胞中高表达，敲减chd8可致斑马鱼前脑和中脑区域小胶质细胞激活数量增加，M2型激活标志物上升而M1型下降，诱导小胶质细胞发生M1型激活可挽救chd8缺陷导致的神经细胞增多的表型；此外，小胶质细胞增殖增加并向神经祖细胞聚集。这些结果提示chd8缺陷可能导致小胶质细胞处于抗炎状态并与神经祖细胞的相互作用发生改变。由此，我们推测chd8可能在小胶质细胞的激活和增殖中扮演重要角色。本项目拟探讨(1)chd8在小胶质细胞激活和增殖中的作用和调控机制；(2)chd8调控小胶质细胞参与神经祖细胞增殖分化、神经元凋亡和突触修剪的分子细胞机制；(3)小胶质细胞异常激活和增殖与自闭症行为之间的关系。本项目的展开将为明晰小胶质细胞的调控机制和自闭症发病机制打下基础。

Abnormal activation and proliferation of microglia during development of central nervous system is an important pathogenic factor accounting for many neurodevelopmental diseases, however, little is known about the underlying mechanisms. We recently found that autism high risk gene chd8 is expressed in microglia cells. Knockdown of chd8 resulted in the increase of activated microglia cells in the forebrain region and midbrain region and the increase of M2 activating markers and decrease of M1 activating markers. Induction of microglia M1 activation was able to rescue the abnormal increase of neural cells caused by chd8 deficiency. Moreover, we found that the proliferation of microglia was increased and microglia was recruited to neural progenitor cells. These results indicate that chd8 deficiency may result in anti-inflammatory status of microglia and interaction between microglia and neural progenitor is changed. Therefore, we speculate that chd8 plays an important role in activation and proliferation of microglia. Our project is going to study 1. the role of chd8 in activation and proliferation of microglia; 2. the molecular and cellular mechanisms underlying the regulation of chd8 in modulation of microglia to take part in neurogenesis, neural apoptosis and synaptic pruning; 3. the relationship between abnormal activation and autism-like behaviors. Our project will lay the foundation for understanding the regulatory mechanism and autism pathogenesis.