Early Postnatal Lipopolysaccharide Exposure Leads to Enhanced Neurogenesis and Impaired Communicative Functions in Rats

Perinatal infection is a well-identified risk factor for a number of neurodevelopmental disorders, including brain white matter injury (WMI) and Autism Spectrum Disorders (ASD). The underlying mechanisms by which early life inflammatory events cause aberrant neural, cytoarchitectural, and network organization, remain elusive. This study is aimed to investigate how systemic lipopolysaccharide (LPS)-induced neuroinflammation affects microglia phenotypes and early neural developmental events in rats. We show here that LPS exposure at early postnatal day 3 leads to a robust microglia activation which is characterized with mixed microglial proinflammatory (M1) and anti-inflammatory (M2) phenotypes. More specifically, we found that microglial M1 markers iNOS and MHC-II were induced at relatively low levels in a regionally restricted manner, whereas M2 markers CD206 and TGFβ were strongly upregulated in a sub-set of activated microglia in multiple white and gray matter structures. This unique microglial response was associated with a marked decrease in naturally occurring apoptosis, but an increase in cell proliferation in the subventricular zone (SVZ) and the dentate gyrus (DG) of hippocampus. LPS exposure also leads to a significant increase in oligodendrocyte lineage population without causing discernible hypermyelination. Moreover, LPS-exposed rats exhibited significant impairments in communicative and cognitive functions. These findings suggest a possible role of M2-like microglial activation in abnormal neural development that may underlie ASD-like behavioral impairments.

围产期感染是多种神经发育障碍的明确危险因素，包括脑白质损伤（WMI）与孤独症谱系障碍（ASD）。生命早期炎症事件引发异常神经、细胞结构及网络构建的潜在机制仍未阐明。本研究旨在探讨全身性脂多糖（LPS）诱导的神经炎症如何影响大鼠的小胶质细胞表型与早期神经发育事件。本研究结果显示，出生后第3天暴露于LPS可引发强烈的小胶质细胞活化，其特征为混合了促炎（M1）与抗炎（M2）表型的小胶质细胞群体。更具体而言，我们发现小胶质细胞M1标志物诱导型一氧化氮合酶（iNOS）与主要组织相容性复合体II类（MHC-II）以区域限制性方式被低水平诱导；而M2标志物CD206与转化生长因子β（TGF-β）则在多脑区白质与灰质结构中的活化小胶质细胞亚群中被显著上调。这种独特的小胶质细胞反应与生理性细胞凋亡的显著减少相关，同时可使侧脑室下区（SVZ）与海马齿状回（DG）的细胞增殖水平升高。LPS暴露还可导致少突胶质细胞谱系细胞群显著增加，但未引发明显的髓鞘过度增生。此外，暴露于LPS的大鼠表现出显著的社交与认知功能损伤。上述研究结果提示，类M2表型的小胶质细胞活化可能参与异常神经发育过程，这或许是类ASD行为缺陷的潜在机制。