Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
Sci Transl Med. 2023 Nov 8;15(721):eade1283. doi: 10.1126/scitranslmed.ade1283.
Inflammation early in life is a clinically established risk factor for autism spectrum disorders and schizophrenia, yet the impact of inflammation on human brain development is poorly understood. The cerebellum undergoes protracted postnatal maturation, making it especially susceptible to perturbations contributing to the risk of developing neurodevelopmental disorders. Here, using single-cell genomics of postmortem cerebellar brain samples, we characterized the postnatal development of cerebellar neurons and glia in 1- to 5-year-old children, comparing individuals who had died while experiencing inflammation with those who had died as a result of an accident. Our analyses revealed that inflammation and postnatal cerebellar maturation are associated with extensive, overlapping transcriptional changes primarily in two subtypes of inhibitory neurons: Purkinje neurons and Golgi neurons. Immunohistochemical analysis of a subset of these postmortem cerebellar samples revealed no change to Purkinje neuron soma size but evidence for increased activation of microglia in those children who had experienced inflammation. Maturation-associated and inflammation-associated gene expression changes included genes implicated in neurodevelopmental disorders. A gene regulatory network model integrating cell type-specific gene expression and chromatin accessibility identified seven temporally specific gene networks in Purkinje neurons and suggested that inflammation may be associated with the premature down-regulation of developmental gene expression programs.
生命早期的炎症是自闭症谱系障碍和精神分裂症的一个临床确立的风险因素，但炎症对人类大脑发育的影响还知之甚少。小脑在后生期经历长期成熟，使其特别容易受到导致神经发育障碍风险的干扰。在这里，我们使用死后小脑脑样本的单细胞基因组学，对 1 至 5 岁儿童的小脑神经元和神经胶质的出生后发育进行了特征描述，将经历炎症而死亡的个体与因意外而死亡的个体进行了比较。我们的分析表明，炎症和出生后小脑成熟与广泛的、重叠的转录变化有关，主要发生在两种抑制性神经元亚型中：浦肯野神经元和高尔基神经元。对这些死后小脑样本的一部分进行免疫组织化学分析显示，浦肯野神经元体大小没有变化，但在经历炎症的儿童中，小胶质细胞的激活证据增加。与成熟相关和与炎症相关的基因表达变化包括与神经发育障碍相关的基因。一个整合细胞类型特异性基因表达和染色质可及性的基因调控网络模型，在浦肯野神经元中确定了七个具有时间特异性的基因网络，并表明炎症可能与发育基因表达程序的过早下调有关。
