Aria Francesca, Bonini Sara A, Cattaneo Valentina, Premoli Marika, Mastinu Andrea, Maccarinelli Giuseppina, Memo Maurizio
Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
Brain Sci. 2020 Sep 7;10(9):620. doi: 10.3390/brainsci10090620.
Aberrant immune activity during neurodevelopment could participate in the generation of neurological dysfunctions characteristic of several neurodevelopmental disorders (NDDs). Numerous epidemiological studies have shown a link between maternal infections and NDDs risk; animal models of maternal immune activation (MIA) have confirmed this association. Activation of maternal immune system during pregnancy induces behavioral and functional alterations in offspring but the biological mechanisms at the basis of these effects are still poorly understood. In this study, we investigated the effects of prenatal lipopolysaccharide (LPS) exposure in peripheral and central inflammation, cortical cytoarchitecture and behavior of offspring (LPS-mice). LPS-mice reported a significant increase in interleukin-1β (IL-1β) serum level, glial fibrillary acidic protein (GFAP)- and ionized calcium-binding adapter molecule 1 (Iba1)-positive cells in the cortex. Furthermore, cytoarchitecture analysis in specific brain areas, showed aberrant alterations in minicolumns' organization in LPS-mice adult brain. In addition, we demonstrated that LPS-mice presented behavioral alterations throughout life. In order to better understand biological mechanisms whereby LPS induced these alterations, dams were treated with meloxicam. We demonstrated for the first time that exposure to LPS throughout pregnancy induces structural permanent alterations in offspring brain. LPS-mice also present severe behavioral impairments. Preventive treatment with meloxicam reduced inflammation in offspring but did not rescue them from structural and behavioral alterations.
神经发育过程中的异常免疫活动可能参与了几种神经发育障碍（NDDs）所特有的神经功能障碍的产生。大量流行病学研究表明，母亲感染与NDDs风险之间存在联系；母亲免疫激活（MIA）的动物模型证实了这种关联。孕期母亲免疫系统的激活会导致后代出现行为和功能改变，但这些影响背后的生物学机制仍知之甚少。在本研究中，我们调查了产前暴露于脂多糖（LPS）对后代（LPS小鼠）外周和中枢炎症、皮质细胞结构及行为的影响。LPS小鼠的血清白细胞介素-1β（IL-1β）水平、皮质中胶质纤维酸性蛋白（GFAP）和离子钙结合衔接分子1（Iba1）阳性细胞显著增加。此外，对特定脑区的细胞结构分析显示，LPS小鼠成年大脑的微小柱组织存在异常改变。另外，我们证明LPS小鼠一生都存在行为改变。为了更好地理解LPS诱导这些改变的生物学机制，对母鼠用美洛昔康进行治疗。我们首次证明，孕期全程暴露于LPS会导致后代大脑发生结构性永久性改变。LPS小鼠还存在严重的行为障碍。用美洛昔康进行预防性治疗可减轻后代的炎症，但无法使其免于结构和行为改变。
