Department of Psychiatry, University of California San Diego, CA 9500 Gilman Drive, La Jolla, CA 92093, United States; Department of Psychology, California State University San Bernardino, 5500 University Parkway, San Bernardino, CA 92407, United States.
Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92093, United States.
Neurobiol Dis. 2019 May;125:211-218. doi: 10.1016/j.nbd.2019.01.025. Epub 2019 Feb 2.
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.
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.
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.
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.
流行病学研究表明，孕妇在怀孕期间暴露于病毒或细菌感染会增加神经发育障碍（如自闭症谱系障碍（ASD）和精神分裂症）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。
本研究调查了母体免疫激活（MIA）在小鼠中如何影响成年额叶皮质中的基因表达，以及这些分子变化如何与认知灵活性缺陷、社会行为减少以及 ASD 中常见的重复行为增加相关。在 E12.5 时向母体注射聚肌胞苷酸（20mg/kg），并在成年时测试后代的社交接近行为、重复梳理行为和概率反转学习（n=8 辆对照车；n=9 辆 Poly（I：C））。我们采用下一代高通量 mRNA 测序（RNA-seq）全面研究了母体暴露于聚肌胞苷酸后成年后代额叶皮质的转录组谱。
与对照组相比，孕期暴露于聚肌胞苷酸会损害 MIA 后代的概率反转学习和社交接近能力。我们发现 MIA 对 24 个基因的表达有长期影响，包括涉及谷氨酸能神经递质传递、mTOR 信号和钾离子通道活性的基因。基因表达与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。
这些发现表明，MIA 可导致小鼠认知灵活性受损，类似于 ASD 个体的表现，并且这些损伤与额叶皮质中的基因表达改变有关。
