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 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 sub-sequence effects of 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 embryonic day 15. LPS significantly elevated pro-inflammatory cytokines in maternal serum, amniotic fluid, and fetal brain at 4 h, and levels decreased but remained elevated at 24 h. Offspring born to LPS-dams exhibited reduced social 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 possible molecular mechanisms by which MIA effects 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.母体免疫激活（Maternal immune activation, MIA）是精神分裂症与孤独症发病的风险因素。孕期感染可激活母体免疫系统并改变胎儿宫内环境，进而对子代的中枢神经系统（Central Nervous System, CNS）功能与行为产生后续影响，但感染诱导的胎儿发育异常与神经精神疾病风险之间的细胞与分子关联仍不明晰。本研究针对孕15天经腹腔注射（0.25 mg/kg）脂多糖（Lipopolysaccharide, LPS）的斯普拉格-道利（Sprague-Dawley, SD）大鼠，探究了母体免疫激活对子代的免疫学、分子生物学与行为学影响。脂多糖处理后4小时，母体血清、羊水及胎儿脑组织中的促炎细胞因子水平显著升高；24小时时该水平有所下降但仍维持在较高水平。脂多糖暴露母鼠所产子代在幼年及青年阶段均表现出社交与探索行为受损。为阐明母体免疫激活影响胎儿脑组织的潜在分子机制，本研究对母体经脂多糖处理后4小时的胎儿脑组织进行了全基因组微阵列分析。我们在限定的功能类别中观察到3285个基因表达失调：细胞应激与细胞死亡相关基因的mRNA表达上调，而发育调控及脑特异性基因（尤其是调控γ-氨基丁酸能中间神经元迁移的基因）的表达则出现下调。