López-Aranda Manuel F, Chattopadhyay Ishanu, Boxx Gayle M, Fraley Elizabeth R, Silva Tawnie K, Zhou Miou, Phan Miranda, Herrera Isaiah, Taloma Sunrae, Mandanas Rochelle, Bach Karen, Gandal Michael, Geschwind Daniel H, Cheng Genhong, Rzhetsky Andrey, White Stephanie A, Silva Alcino J
Departments of Neurobiology, Psychology, and Psychiatry, Integrative Center for Learning and Memory, and Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Medicine and Human Genetics, Section of Computational Biomedicine and Biomedical Data Science, and Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL, USA.
Sci Adv. 2021 Sep 17;7(38):eabf2073. doi: 10.1126/sciadv.abf2073.
There is growing evidence that prenatal immune activation contributes to neuropsychiatric disorders. Here, we show that early postnatal immune activation resulted in profound impairments in social behavior, including in social memory in adult male mice heterozygous for a gene responsible for tuberous sclerosis complex (), a genetic disorder with high prevalence of autism. Early postnatal immune activation did not affect either wild-type or female mice. We demonstrate that these memory deficits are caused by abnormal mammalian target of rapamycin–dependent interferon signaling and impairments in microglia function. By mining the medical records of more than 3 million children followed from birth, we show that the prevalence of hospitalizations due to infections in males (but not in females) is associated with future development of autism spectrum disorders (ASD). Together, our results suggest the importance of synergistic interactions between strong early postnatal immune activation and mutations associated with ASD.
越来越多的证据表明，产前免疫激活会导致神经精神疾病。在此，我们表明，产后早期免疫激活会导致成年雄性小鼠社会行为出现严重缺陷，包括对患有结节性硬化症（一种自闭症患病率很高的遗传性疾病）的基因杂合子的成年雄性小鼠的社会记忆。产后早期免疫激活对野生型或雌性小鼠均无影响。我们证明，这些记忆缺陷是由异常的哺乳动物雷帕霉素靶蛋白依赖性干扰素信号传导和小胶质细胞功能受损引起的。通过挖掘300多万名从出生就开始跟踪的儿童的病历，我们发现男性（而非女性）因感染而住院的患病率与自闭症谱系障碍（ASD）的未来发展有关。总之，我们的结果表明，产后早期强烈免疫激活与ASD相关突变之间的协同相互作用很重要。
