Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences Kraków, Poland.
Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences Kraków, Poland.
Front Cell Neurosci. 2015 Mar 12;9:82. doi: 10.3389/fncel.2015.00082. eCollection 2015.
Several lines of evidence suggest that the dysregulation of the immune system is an important factor in the development of depression. Microglia are the resident macrophages of the central nervous system and a key player in innate immunity of the brain. We hypothesized that prenatal stress (an animal model of depression) as a priming factor could affect microglial cells and might lead to depressive-like disturbances in adult male rat offspring. We investigated the behavioral changes (sucrose preference test, Porsolt test), the expression of C1q and CD40 mRNA and the level of microglia (Iba1 positive) in 3-month-old control and prenatally stressed male offspring rats. In addition, we characterized the morphological and biochemical parameters of potentially harmful (NO, iNOS, IL-1β, IL-18, IL-6, TNF-α, CCL2, CXCL12, CCR2, CXCR4) and beneficial (insulin-like growth factor-1 (IGF-1), brain derived neurotrophic factor (BDNF)) phenotypes in cultures of microglia obtained from the cortices of 1-2 days old control and prenatally stressed pups. The adult prenatally stressed rats showed behavioral (anhedonic- and depression-like) disturbances, enhanced expression of microglial activation markers and an increased number of Iba1-immunopositive cells in the hippocampus and frontal cortex. The morphology of glia was altered in cultures from prenatally stressed rats, as demonstrated by immunofluorescence microscopy. Moreover, in these cultures, we observed enhanced expression of CD40 and MHC II and release of pro-inflammatory cytokines, including IL-1β, IL-18, TNF-α and IL-6. Prenatal stress significantly up-regulated levels of the chemokines CCL2, CXCL12 and altered expression of their receptors, CCR2 and CXCR4 while IGF-1 production was suppressed in cultures of microglia from prenatally stressed rats. Our results suggest that prenatal stress may lead to excessive microglia activation and contribute to the behavioral changes observed in depression in adulthood.
有几条证据表明，免疫系统的失调是抑郁症发展的一个重要因素。小胶质细胞是中枢神经系统的常驻巨噬细胞，也是大脑固有免疫的关键参与者。我们假设产前应激（一种抑郁症的动物模型）作为启动因素可以影响小胶质细胞，并可能导致成年雄性大鼠后代出现类似抑郁的紊乱。我们研究了行为变化（蔗糖偏好测试、Porsolt 测试）、C1q 和 CD40mRNA 的表达以及 3 个月大的对照组和产前应激雄性后代大鼠小胶质细胞（Iba1 阳性）的水平。此外，我们还描述了从小鼠皮质中获得的小胶质细胞培养物的潜在有害（NO、iNOS、IL-1β、IL-18、IL-6、TNF-α、CCL2、CXCL12、CCR2、CXCR4）和有益（胰岛素样生长因子-1 (IGF-1)、脑源性神经营养因子 (BDNF))表型的形态和生化参数。成年产前应激大鼠表现出行为（快感缺失和抑郁样）紊乱、小胶质细胞激活标志物表达增强以及海马体和前额皮质中 Iba1 免疫阳性细胞数量增加。产前应激大鼠的神经胶质细胞形态发生改变，这可以通过免疫荧光显微镜观察到。此外，在这些培养物中，我们观察到 CD40 和 MHC II 的表达增强以及包括 IL-1β、IL-18、TNF-α 和 IL-6 在内的促炎细胞因子的释放。产前应激显著上调了趋化因子 CCL2、CXCL12 的水平，并改变了其受体 CCR2 和 CXCR4 的表达，而 IGF-1 的产生在产前应激大鼠的小胶质细胞培养物中受到抑制。我们的结果表明，产前应激可能导致小胶质细胞过度激活，并导致成年期观察到的抑郁行为变化。
