Prenatal Activation of Microglia Induces Delayed Impairment of Glutamatergic Synaptic Function
Prenatal Activation of Microglia Induces Delayed Impairment of Glutamatergic Synaptic Function
复制标题
小胶质细胞的产前激活导致谷氨酸能突触功能迟发性损伤
作者：
A. Roumier;O. Pascual;C. Béchade;S. Wakselman;J. Poncer;E. Réal;A. Triller;A. Bessis
背景流行病学研究已将孕期母体感染与子代神经精神障碍的后期发展联系起来。在小鼠中，胚胎发育期间的实验性炎症会损害成年后的行为和认知表现。突触功能障碍可能是认知障碍的根源，然而，产前炎症和突触缺陷之间的联系仍有待确定。方法/主要发现在这项研究中，我们发现，产前小胶质细胞功能的改变，包括炎症，会导致成人迟发性突触功能障碍。DAP12是一种在出生前后表达的小胶质信号蛋白，其突变在人类中会导致以早期痴呆为特征的Nasu-Hakola病。我们目前报道，在携带DAP12基因功能缺失突变的小鼠(DAP12KI小鼠)中，突触兴奋电流显示AMPA的相对贡献增强。此外，没有小胶质细胞培养的DAP12KI P0幼鼠的神经元也出现了类似的突触变化，这表明出生前小胶质细胞功能障碍可能会影响成年鼠的突触功能。由于我们观察到DAP12KI小胶质细胞过度表达炎性蛋白IL1β、IL6和NOS2，我们分析了药物诱导的产前炎症对突触功能的影响。母体注射脂多糖可诱导出生时小胶质细胞的激活和成年后代谷氨酸能突触的改变。最后，发炎母亲所生的新生儿的神经元以及培养中没有小胶质细胞的神经元也显示出神经元活动的改变。结论/意义我们的结果表明，胎儿期炎症足以引起迟发性突触改变。我们认为，这些由产前激活的小胶质细胞触发的改变为产前炎症引起的神经精神缺陷提供了细胞学基础。
Background Epidemiological studies have linked maternal infection during pregnancy to later development of neuropsychiatric disorders in the offspring. In mice, experimental inflammation during embryonic development impairs behavioral and cognitive performances in adulthood. Synaptic dysfunctions may be at the origin of cognitive impairments, however the link between prenatal inflammation and synaptic defects remains to be established. Methodology/Principal Findings In this study, we show that prenatal alteration of microglial function, including inflammation, induces delayed synaptic dysfunction in the adult. DAP12 is a microglial signaling protein expressed around birth, mutations of which in the human induces the Nasu-Hakola disease, characterized by early dementia. We presently report that synaptic excitatory currents in mice bearing a loss-of-function mutation in the DAP12 gene (DAP12KI mice) display enhanced relative contribution of AMPA. Furthermore, neurons from DAP12KI P0 pups cultured without microglia develop similar synaptic alterations, suggesting that a prenatal dysfunction of microglia may impact synaptic function in the adult. As we observed that DAP12KI microglia overexpress genes for IL1β, IL6 and NOS2, which are inflammatory proteins, we analyzed the impact of a pharmacologically-induced prenatal inflammation on synaptic function. Maternal injection of lipopolysaccharides induced activation of microglia at birth and alteration of glutamatergic synapses in the adult offspring. Finally, neurons cultured from neonates born to inflamed mothers and cultured without microglia also displayed altered neuronal activity. Conclusion/Significance Our results demonstrate that prenatal inflammation is sufficient to induce synaptic alterations with delay. We propose that these alterations triggered by prenatal activation of microglia provide a cellular basis for the neuropsychiatric defects induced by prenatal inflammation.
影响因子：
56.9
作者：
E. Beattie;D. Stellwagen;W. Morishita;J. Bresnahan;Byeong Keun Ha;M. von Zastrow;M. Beattie;R. Malenka-R
通讯作者：
E. Beattie;D. Stellwagen;W. Morishita;J. Bresnahan;Byeong Keun Ha;M. von Zastrow;M. Beattie;R. Malenka-R
DOI：
10.1111/j.1469-7610.1988.tb00714.x
发表时间：
1988-05
期刊：
Journal of child psychology and psychiatry, and allied disciplines
影响因子：
--
作者：
Christopher Gillberg
通讯作者：
Christopher Gillberg
影响因子：
6.6
作者：
Brown, AS
通讯作者：
Brown, AS