Pangrazzi Luca, Cerilli Enrica, Balasco Luigi, Khurshid Chrow, Tobia Caterina, Dall'O' Ginevra Matilde, Chelini Gabriele, Perini Samuel, Filosi Michele, Barbieri Anna, Ravizza Teresa, Vezzani Annamaria, Provenzano Giovanni, Pastore Anna, Weinberger Birgit, Rubert Josep, Domenici Enrico, Bozzi Yuri
CIMeC - Center for Mind/Brain Sciences, University of Trento, Piazza della Manifattura 1 38068 Rovereto, Trento, Italy; Institute for Biomedical Aging Research, Universität Innsbruck, Rennweg 10 6020 Innsbruck, Austria.
CIMeC - Center for Mind/Brain Sciences, University of Trento, Piazza della Manifattura 1 38068 Rovereto, Trento, Italy.
Brain Behav Immun. 2025 Jul;127:57-71. doi: 10.1016/j.bbi.2025.02.030. Epub 2025 Feb 27.
Autism Spectrum Disorder (ASD) is a highly prevalent neurodevelopmental condition characterized by social communication deficits and repetitive/restricted behaviors. Several studies showed that oxidative stress and inflammation may contribute to ASD. Indeed, increased levels of oxygen radicals and pro-inflammatory molecules were described in the brain and peripheral blood of persons with ASD and mouse models. Despite this, a potential direct connection between oxidative stress and inflammation within specific brain areas and ASD-related behaviors has not been investigated in detail yet. Here, we used RT-qPCR, RNA sequencing, metabolomics, immunohistochemistry, and flow cytometry to show that pro-inflammatory molecules were increased in the cerebellum and periphery of mice lacking Cntnap2, a robust model of ASD. In parallel, oxidative stress was present in the cerebellum of mutant animals. Systemic treatment with N-acetyl-cysteine (NAC) rescued cerebellar oxidative stress, inflammation, as well as motor and social impairments in Cntnap2 mice, concomitant with enhanced function of microglia cells in NAC-treated mutants. Intriguingly, social deficits, cerebellar inflammation, and microglia dysfunction were induced by NAC in Cntnap2 animals. Our findings suggest that the interplay between oxidative stress and inflammation accompanied by genetic vulnerability may underlie ASD-related behaviors in Cntnap2 mutant mice.
自闭症谱系障碍（ASD）是一种高度普遍的神经发育疾病，其特征为社交沟通缺陷和重复/受限行为。多项研究表明，氧化应激和炎症可能与ASD有关。事实上，在ASD患者和小鼠模型的大脑及外周血中，氧自由基和促炎分子的水平有所升高。尽管如此，特定脑区的氧化应激与炎症和ASD相关行为之间的潜在直接联系尚未得到详细研究。在此，我们使用逆转录定量聚合酶链反应（RT-qPCR）、RNA测序、代谢组学、免疫组织化学和流式细胞术来表明，在缺乏Cntnap2的小鼠（一种可靠的ASD模型）的小脑和外周中，促炎分子增加。同时，突变动物的小脑中存在氧化应激。用N-乙酰半胱氨酸（NAC）进行全身治疗可挽救Cntnap2小鼠的小脑氧化应激、炎症以及运动和社交障碍，同时增强NAC处理的突变体中小胶质细胞的功能。有趣的是，NAC在Cntnap2动物中诱导了社交缺陷、小脑炎症和小胶质细胞功能障碍。我们的研究结果表明，氧化应激与炎症之间的相互作用以及遗传易感性可能是Cntnap2突变小鼠中ASD相关行为的基础。
