Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies
Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies
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DOI：
10.1016/j.bbi.2015.09.015
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发表时间：
2016-07-01
影响因子：
15.1
通讯作者：
Engler, Harald
中科院分区：
文献类型：
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作者：
Giovanoli, Sandra;Weber-Stadlbauer, Ulrike;Engler, Harald
产前暴露于感染性或炎症性侮辱会增加晚年患神经精神障碍的风险，包括精神分裂症、双相情感障碍和自闭症。这些大脑疾病的特征还包括突触前和突触后的缺陷。利用一种成熟的母亲暴露于病毒模拟物聚核苷-聚核糖核酸[Poly(I：C)]的小鼠模型，我们研究了产前免疫激活是否可能导致青春期和成年后代海马区突触结构的缺陷。基于小胶质细胞在突触修剪中被广泛认可的作用，我们进一步探索了接触聚(I：C)的母亲和对照母亲的后代中突触缺陷和小胶质细胞异常之间的可能联系。我们发现，孕期免疫激活导致成人出现突触前海马区缺陷(通过突触素和巴松管密度进行评估)。早期的侮辱进一步导致了青春期突触后海马区的缺陷(根据PSD95和SynGAP密度的评估)，其中一些一直持续到成年。相比之下，产前免疫激活没有改变小胶质细胞(或星形胶质细胞)的密度，也没有改变它们的激活表型。产前操作也没有引起持续性全身炎症的迹象。尽管没有明显的神经胶质异常或全身炎症，暴露于产前免疫激活的成年后代显示出海马区IL-1β水平升高。综上所述，我们的研究结果表明，在没有小胶质细胞异常或全身炎症的情况下，出生后大脑成熟过程中可能会出现年龄依赖性突触缺陷和异常的促炎细胞因子表达。(C)2015 Elsevier Inc.保留所有权利。
Prenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre- and postsynaptic deficits. Using a well-established mouse model of maternal exposure to the viral mimetic polyriboinosinic-polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I: C)-exposed and control mothers. We found that prenatal immune activation induced an adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early-life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial anomalies or systemic inflammation, adult offspring exposed to prenatal immune activation displayed increased hippocampal IL-1 beta levels. Taken together, our findings demonstrate that age dependent synaptic deficits and abnormal pro-inflammatory cytokine expression can occur during postnatal brain maturation in the absence of microglial anomalies or systemic inflammation. (C) 2015 Elsevier Inc. All rights reserved.