Maternal immune activation impairs cognitive flexibility and alters transcription in frontal cortex
Maternal immune activation impairs cognitive flexibility and alters transcription in frontal cortex
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DOI：
10.1016/j.nbd.2019.01.025
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发表时间：
2019-05-01
影响因子：
6.1
通讯作者：
Powell, Susan B.
中科院分区：
文献类型：
--
作者：
Amodeo, Dionisio A.;Lai, Chi-Yu;Powell, Susan B.
背景：流行病学研究表明，怀孕期间产前接触病毒或细菌感染会增加患自闭症谱系障碍（ASD）和精神分裂症等神经发育障碍的风险。目前尚不清楚母体免疫反应的激活如何与潜在的遗传因素相互作用，从而影响观察到的 ASD 表型。方法：当前的研究调查了小鼠的母体免疫激活 (MIA) 如何影响成年期额叶皮层的基因表达，以及这些分子变化如何与认知灵活性和社会行为的缺陷以及 ASD 中常见的重复行为的增加相关。在 E12.5 时对母鼠施用 Poly(I:C) (20 mg/kg)，并测试后代的社交接近行为、重复梳理行为和成年期的概率逆转学习（n = 8 个载体；n = 9 个 Poly(I:C)）。我们采用下一代高通量 mRNA 测序 (RNA-seq) 来全面研究暴露于 Poly(I:C) 的母鼠成年后代额叶皮层的转录组谱。结果：与对照组相比，妊娠期间暴露于 Poly(I:C) 会损害 MIA 后代的概率逆转学习并减少社交行为。我们发现 MIA 对 24 个基因的表达有长期影响，包括参与谷氨酸能神经传递、mTOR 信号传导和钾离子通道活性的基因。基因表达和特定行为测量之间的相关性提供了对可能导致 ASD 样行为改变的基因的深入了解。结论：这些发现表明，MIA 可能导致小鼠认知灵活性受损，类似于 ASD 个体所表现出的情况，并且这些损害与额叶皮层基因表达的改变有关。
Background: Epidemiological studies suggest that the risk of neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia is increased by prenatal exposure to viral or bacterial infection during pregnancy. It is still unclear how activation of the maternal immune response interacts with underlying genetic factors to influence observed ASD phenotypes.Methods: The current study investigated how maternal immune activation (MIA) in mice impacts gene expression in the frontal cortex in adulthood, and how these molecular changes relate to deficits in cognitive flexibility and social behavior, and increases in repetitive behavior that are prevalent in ASD. Poly(I:C) (20 mg/kg) was administered to dams on E12.5 and offspring were tested for social approach behavior, repetitive grooming, and probabilistic reversal learning in adulthood (n = 8 vehicle; n = 9 Poly(I:C)). We employed next-generation high-throughput mRNA sequencing (RNA-seq) to comprehensively investigate the transcriptome profile in frontal cortex of adult offspring of Poly(I:C)-exposed dams.Results: Exposure to poly(I:C) during gestation impaired probabilistic reversal learning and decreased social approach in MIA offspring compared to controls. We found long-term effects of MIA on expression of 24 genes, including genes involved in glutamatergic neurotransmission, mTOR signaling and potassium ion channel activity. Correlations between gene expression and specific behavioral measures provided insight into genes that may be responsible for ASD-like behavioral alterations.Conclusions: These findings suggest that MIA can lead to impairments in cognitive flexibility in mice similar to those exhibited in ASD individuals, and that these impairments are associated with altered gene expression in frontal cortex.