The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, CA, United States of America.
Department of Neurosciences, University of California, San Diego School of Medicine, San Diego, CA, United States of America.
PLoS One. 2021 Mar 18;16(3):e0248771. doi: 10.1371/journal.pone.0248771. eCollection 2021.
Since 2012, studies in mice, rats, and humans have suggested that abnormalities in purinergic signaling may be a final common pathway for many genetic and environmental causes of autism spectrum disorder (ASD). The current study in mice was conducted to characterize the bioenergetic, metabolomic, breathomic, and behavioral features of acute hyperpurinergia triggered by systemic injection of the purinergic agonist and danger signal, extracellular ATP (eATP). Responses were studied in C57BL/6J mice in the maternal immune activation (MIA) model and controls. Basal metabolic rates and locomotor activity were measured in CLAMS cages. Plasma metabolomics measured 401 metabolites. Breathomics measured 98 volatile organic compounds. Intraperitoneal eATP dropped basal metabolic rate measured by whole body oxygen consumption by 74% ± 6% (mean ± SEM) and rectal temperature by 6.2˚ ± 0.3˚C in 30 minutes. Over 200 metabolites from 37 different biochemical pathways where changed. Breathomics showed an increase in exhaled carbon monoxide, dimethylsulfide, and isoprene. Metabolomics revealed an acute increase in lactate, citrate, purines, urea, dopamine, eicosanoids, microbiome metabolites, oxidized glutathione, thiamine, niacinamide, and pyridoxic acid, and decreased folate-methylation-1-carbon intermediates, amino acids, short and medium chain acyl-carnitines, phospholipids, ceramides, sphingomyelins, cholesterol, bile acids, and vitamin D similar to some children with ASD. MIA animals were hypersensitive to postnatal exposure to eATP or poly(IC), which produced a rebound increase in body temperature that lasted several weeks before returning to baseline. Acute hyperpurinergia produced metabolic and behavioral changes in mice. The behaviors and metabolic changes produced by ATP injection were associated with mitochondrial functional changes that were profound but reversible.
自 2012 年以来，对小鼠、大鼠和人类的研究表明，嘌呤能信号异常可能是自闭症谱系障碍（ASD）许多遗传和环境病因的最终共同途径。本研究在 MIA 模型和对照的 C57BL/6J 小鼠中进行，以描述全身注射嘌呤能激动剂和危险信号细胞外三磷酸腺苷（eATP）引起的急性高嘌呤能的生物能量学、代谢组学、呼吸组学和行为特征。在 CLAMS 笼中测量基础代谢率和运动活动。血浆代谢组学测量了 401 种代谢物。呼吸组学测量了 98 种挥发性有机化合物。腹腔内 eATP 在 30 分钟内使全身耗氧量测量的基础代谢率降低了 74%±6%（平均值±SEM），直肠温度降低了 6.2˚±0.3˚C。37 种不同生化途径中有 200 多种代谢物发生变化。呼吸组学显示呼出的一氧化碳、二甲基硫和异戊二烯增加。代谢组学显示乳酸、柠檬酸、嘌呤、尿素、多巴胺、类二十烷酸、微生物组代谢物、氧化谷胱甘肽、硫胺素、烟酰胺和吡哆醛酸的急性增加，以及叶酸甲基化-1-碳中间产物、氨基酸、短链和中链酰基肉碱、磷脂、神经酰胺、鞘脂、胆固醇、胆汁酸和维生素 D 的减少，与一些 ASD 儿童相似。MIA 动物对出生后暴露于 eATP 或 poly(IC) 更为敏感，这会导致体温反弹增加，持续数周后才恢复到基线。急性高嘌呤能在小鼠中产生代谢和行为变化。ATP 注射引起的行为和代谢变化与线粒体功能变化有关，这些变化虽然深刻但却是可逆的。
