The interplay between oxidative stress and inflammation supports autistic-related behaviors in Cntnap2 knockout mice
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<sup>-/-</sup> 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<sup>+/+</sup> 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.
Authors
- Giovanni Provenzano (ORCID: https://orcid.org/0000-0001-7160-4184)
- Gabriele Chelini (ORCID: https://orcid.org/0000-0001-6654-4332)
- Enrico Domenici (ORCID: https://orcid.org/0000-0001-7436-6919)
- Luigi Balasco (ORCID: https://orcid.org/0000-0002-5750-8505)
- Enrica Cerilli
- Samuel Perini (ORCID: https://orcid.org/0000-0001-7524-151X)
- Luca Pangrazzi (ORCID: https://orcid.org/0000-0003-0673-4577)
- Anna Barbieri (ORCID: https://orcid.org/0000-0001-5764-9132)
- Josep Rubert (ORCID: https://orcid.org/0000-0002-1634-2334)
- Teresa Ravizza (ORCID: https://orcid.org/0000-0002-9578-018X)
- Birgit Weinberger (ORCID: https://orcid.org/0000-0002-7084-946X)
- Anna Pastore (ORCID: https://orcid.org/0000-0002-0990-9419)
- Yuri Bozzi (ORCID: https://orcid.org/0000-0002-1496-9889)
- Ginevra Matilde Dall‘O’ (ORCID: https://orcid.org/0000-0002-6487-9478)
- Chrow Khurshid
- Annamaria Vezzani (ORCID: https://orcid.org/0000-0003-0573-6175)
- Caterina Tobia
- Michele Filosi (ORCID: https://orcid.org/0000-0002-3872-347X)
Institutions
- University of Kirkuk (IQ)
- Università Cattolica del Sacro Cuore (IT)
- Universität Innsbruck (AT)
- University of Trento (IT)
- Mario Negri Institute for Pharmacological Research (IT)
- The Microsoft Research - University of Trento Centre for Computational and Systems Biology (IT)
- Bambino Gesù Children's Hospital (IT)
- Wageningen University & Research (NL)
Publication Details
- Journal
- Brain Behavior and Immunity
- Published
- 2025-02-28
- DOI
- https://doi.org/10.1016/j.bbi.2025.02.030
- Citations
- 14
- Primary Topic
- Autism Spectrum Disorder Research
- Type
- article
- Field-Weighted Citation Impact
- 20.04
Funders
- Università degli Studi di Trento
- Fondazione Umberto Veronesi
- Fondazione Cassa Di Risparmio Di Trento E Rovereto
- Universität Innsbruck
- European Regional Development Fund