Psychobiology Research Laboratory, Mazor Mental Health Center, Akko, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
Psychobiology Research Laboratory, Mazor Mental Health Center, Akko, Israel.
Brain Behav Immun. 2019 Jul;79:207-215. doi: 10.1016/j.bbi.2019.02.002. Epub 2019 Feb 6.
Maternal inflammation during pregnancy is associated with a higher incidence of mental disorders (e.g. schizophrenia and autism) in the offspring. In our study, we investigate the involvement of the NRG-ErbB signaling pathway in rodent fetal brains four hours following maternal immune activation (MIA) insult at two different gestational days (i.e. early vs late). Furthermore, we test the long-term behavioral alteration of the exposed MIA mice at juvenile and adulthood. We demonstrate that MIA at late, but not at early gestation day, altered the expression of NRG1, its receptor ErbB4, and the dopamine D2 receptor four hours post injection of viral or bacterial mimic material in fetal brain. At the behavioral levels, adult late-MIA-exposed female offspring, but not juvenile, display lack preference to a novel object. While working memory alteration observed only in adult male MIA-exposed offspring at late gestation day. In addition, we found that adult females MIA-exposed mice spent more time in the center of the open field than female-saline groups. On the other hand, juvenile male offspring exposed to MIA at early, but not late, gestation day displayed a significant alteration in social interaction. Our results suggest that MIA during late gestation immediately influences the expression levels of the NRG1 and ErbB4 genes, and affects long-term behavioral changes at adulthood. These behavioral changes are time related and sex-specific. Thus, immune activation at late stages of the embryonic brain development initiates the activation of the NRG1-ErbB4 pathway and this disturbance might result in cognitive dysfunction in adulthood.
母体怀孕期间的炎症与后代精神障碍（如精神分裂症和自闭症）的发病率升高有关。在我们的研究中，我们调查了 NRG-ErbB 信号通路在母体免疫激活（MIA）损伤后两个不同的妊娠天数（即早期和晚期）对啮齿动物胎儿大脑的影响。此外，我们还测试了暴露于 MIA 的小鼠在幼年和成年时的长期行为改变。我们发现，晚期 MIA 会改变 NRG1、其受体 ErbB4 和多巴胺 D2 受体的表达，而早期 MIA 则不会，这种改变发生在胎儿大脑注射病毒或细菌模拟物后的四个小时。在行为水平上，只有晚期 MIA 暴露的成年雌性后代而非幼年后代表现出对新物体缺乏偏好。而只有在晚期 MIA 暴露的成年雄性后代中观察到工作记忆改变。此外，我们发现，成年雌性 MIA 暴露的小鼠在开放场中停留的时间比生理盐水组的雌性小鼠更多。另一方面，在早期而非晚期妊娠日暴露于 MIA 的幼年雄性后代表现出社交互动的显著改变。我们的结果表明，晚期妊娠期间的 MIA 会立即影响 NRG1 和 ErbB4 基因的表达水平，并影响成年后的长期行为变化。这些行为变化与时间有关，且具有性别特异性。因此，胚胎大脑发育晚期的免疫激活会引发 NRG1-ErbB4 通路的激活，这种干扰可能导致成年后的认知功能障碍。
