Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response.
Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response.
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DOI：
10.1016/j.bbi.2012.01.015
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发表时间：
2012-05
影响因子：
15.1
通讯作者：
Herkenham, Miles
中科院分区：
文献类型：
--
作者：
Oskvig, Devon B.;Elkahloun, Abdel G.;Johnson, Kory R.;Phillips, Terry M.;Herkenham, Miles
关键词：
母体免疫激活（MIA）是精神分裂症和自闭症发展的危险因素。妊娠期间的感染激活母亲的免疫系统并改变胎儿环境，从而影响后代的CNS功能和行为，但感染诱导的胎儿发育改变与神经精神疾病风险之间的细胞和分子联系尚不清楚。我们研究了MIA在妊娠第15天腹腔注射脂多糖（LPS）的妊娠Sprague-Dawley大鼠的后代的免疫，分子和行为效应。LPS在4 h显著升高母体血清、羊水和胎脑中的促炎细胞因子水平，并且在24 h水平降低但仍升高。后代出生的LPS治疗的大坝表现出减少社会偏好和探索行为的青少年和年轻的成年人。在母体LPS后4 h进行胎脑的全基因组微阵列分析以阐明MIA影响胎脑的可能分子机制。我们观察到3，285个基因在有限的功能类别中失调，细胞应激和细胞死亡基因的mRNA表达增加，发育调节和脑特异性基因的表达减少，特别是那些调节GABA能中间神经元的神经元迁移的基因，包括无远端（Dlx）从神经节隆起内的祖细胞池切向迁移到大脑皮层所需的转录因子家族。我们的研究结果提供了一种新的机制，通过这种机制，MIA诱导了关键神经发育基因的广泛下调，包括那些以前与自闭症相关的基因。
Maternal immune activation (MIA) is a risk factor for the development of schizophrenia and autism. Infections during pregnancy activate the mother’s immune system and alter the fetal environment, with consequential effects on CNS function and behavior in the offspring, but the cellular and molecular links between infection-induced altered fetal development and risk for neuropsychiatric disorders are unknown. We investigated the immunological, molecular, and behavioral effects of MIA in the offspring of pregnant Sprague-Dawley rats given an intraperitoneal (0.25 mg/kg) injection of lipopolysaccharide (LPS) on gestational day 15. LPS significantly elevated pro-inflammatory cytokine levels in maternal serum, amniotic fluid, and fetal brain at 4 h, and levels decreased but remained elevated at 24 h. Offspring born to LPS-treated dams exhibited reduced social preference and exploration behaviors as juveniles and young adults. Whole genome microarray analysis of the fetal brain at 4 h post maternal LPS was performed to elucidate the possible molecular mechanisms by which MIA affects the fetal brain. We observed dysregulation of 3,285 genes in restricted functional categories, with increased mRNA expression of cellular stress and cell death genes and reduced expression of developmentally-regulated and brain-specific genes, specifically those that regulate neuronal migration of GABAergic interneurons, including the Distal-less (Dlx) family of transcription factors required for tangential migration from progenitor pools within the ganglionic eminences into the cerebral cortex. Our results provide a novel mechanism by which MIA induces the widespread down-regulation of critical neurodevelopmental genes, including those previously associated with autism.
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影响因子：
3.5
作者：
Di Cristo, G.
通讯作者：
Di Cristo, G.
影响因子：
6
作者：
Carpentier, Pamela A.;Dingman, Andra L.;Palmer, Theo D.
通讯作者：
Palmer, Theo D.
影响因子：
16.2
作者：
Cobos, Inma;Borello, Ugo;Rubenstein, John L. R.
通讯作者：
Rubenstein, John L. R.
DOI：
10.1016/0736-5748(94)00072-b
发表时间：
1995-06-01
影响因子：
1.8
作者：
ARAUJO, DM;COTMAN, CW
通讯作者：
COTMAN, CW
影响因子：
3
作者：
Bilbo SD;Schwarz JM
通讯作者：
Schwarz JM