Mouihate Abdeslam
Department of Physiology, Faculty of Medicine, Health Sciences Centre, Kuwait University Kuwait City, Kuwait.
Front Cell Neurosci. 2016 Jun 30;10:173. doi: 10.3389/fncel.2016.00173. eCollection 2016.
Prenatal immune challenge has been associated with alteration in brain development and plasticity that last into adulthood. We have previously shown that prenatal activation of toll-like receptor 4 by lipopolysaccharide (LPS) induces IL-6-dependent STAT-3 signaling pathway in the fetal brain. Whether this IL-6-dependent activation of fetal brain results in long lasting impact in brain plasticity is still unknown. Furthermore, it has been shown that prenatal LPS heightens the hypothalamic-pituitary-adrenal (HPA) response in adulthood. In the present study we tested whether LPS administration during pregnancy affects neurogenesis in adult male offspring. Because corticosterone, the end-product of HPA axis activity in rats, alters neurogenesis we tested whether this enhanced HPA axis responsiveness in adult male offspring played a role in the long lasting impact of LPS on neurogenesis during adulthood. Pregnant rats were given either LPS, or LPS and an IL-6 neutralizing antibody (IL-6Ab). The newly born neurons were monitored in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus of adult male offspring by monitoring doublecortin and T-box brain protein-2 expression: two well-established markers of newly born neurons. Prenatal LPS decreased the number of newly born neurons in the DG, but not in the SVZ of adult offspring. This decreased number of newly born neurons in the DG was absent when IL-6Ab was co-injected with LPS during pregnancy. Furthermore, administration of a corticosterone receptor blocker, RU-486, to adult offspring blunted the prenatal LPS induced decrease in newly born neurons in the DG. These data suggest that maternally triggered IL-6 plays a crucial role in the long lasting impact of LPS on adult neurogenesis.
产前免疫刺激与持续至成年期的大脑发育和可塑性改变有关。我们之前已经表明，脂多糖（LPS）对Toll样受体4的产前激活会诱导胎儿大脑中依赖白细胞介素6（IL-6）的信号转导和转录激活因子3（STAT-3）信号通路。胎儿大脑中这种依赖IL-6的激活是否会对大脑可塑性产生持久影响仍不清楚。此外，研究表明产前LPS会增强成年期下丘脑-垂体-肾上腺（HPA）轴的反应。在本研究中，我们测试了孕期给予LPS是否会影响成年雄性后代的神经发生。由于皮质酮是大鼠HPA轴活动的终产物，会改变神经发生，我们测试了成年雄性后代中这种增强的HPA轴反应性是否在LPS对成年期神经发生的持久影响中起作用。给怀孕大鼠注射LPS或LPS与IL-6中和抗体（IL-6Ab）。通过监测双皮质素和T-box脑蛋白2的表达来监测成年雄性后代海马体室下区（SVZ）和齿状回（DG）中的新生神经元：这两种是公认的新生神经元标志物。产前LPS减少了成年后代DG中新生神经元的数量，但在SVZ中没有。当孕期将IL-6Ab与LPS共同注射时，DG中新生神经元数量的减少并未出现。此外，给成年后代注射皮质酮受体阻滞剂RU-486可减弱产前LPS诱导的DG中新生神经元数量的减少。这些数据表明，母体触发的IL-6在LPS对成年神经发生的持久影响中起关键作用。
