{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T18:50:54Z","timestamp":1780339854196,"version":"3.54.1"},"reference-count":46,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T00:00:00Z","timestamp":1731542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Trento"},{"name":"Autism Research Institute (ARI) 2021 Research Award"},{"name":"Umberto Veronesi Foundation"},{"name":"Fondazione CARITRO"},{"name":"European Regional Development Fund (ERDF)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Autism spectrum disorder (ASD) includes a range of neurodevelopmental disabilities characterized by social interaction deficits, communication impairments, and repetitive behaviors. Previous studies have shown that pro-inflammatory conditions play a key role in ASD. Despite this, how oxidative stress and inflammation may contribute to ASD-related behaviors is still poorly understood. Here, we reported that increased levels of molecules related to inflammation are present in the cerebellum and peripheral blood (PB) of mice lacking Shank3b, an established model of syndromic ASD. In parallel, immune dysfunction was documented in the bone marrow (BM) and spleens of mutant mice. N-acetylcysteine (NAC) treatment rescued inflammation in the cerebellum and PB and impaired the production of pro-inflammatory molecules in the BM and spleen. In addition, social impairment was counteracted in NAC-treated Shank3b\u2212\/\u2212 animals. Taken together, our results provide clear evidence of the key role of cerebellar oxidative stress and inflammation in the establishment of ASD-related behaviors. Furthermore, our findings underscore the importance of considering ASD as a systemic disorder.<\/jats:p>","DOI":"10.3390\/antiox13111390","type":"journal-article","created":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T08:06:32Z","timestamp":1731571592000},"page":"1390","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["N-Acetylcysteine Counteracts Immune Dysfunction and Autism-Related Behaviors in the Shank3b Mouse Model of Autism Spectrum Disorder"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0673-4577","authenticated-orcid":false,"given":"Luca","family":"Pangrazzi","sequence":"first","affiliation":[{"name":"Institute for Biomedical Aging Research, University of Innsbruck, Rennweg 10, 6020 Innsbruck, Austria"},{"name":"CIMeC\u2014Center for Mind\/Brain Sciences, University of Trento, Piazza della Manifattura 1, 38068 Rovereto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5154-5180","authenticated-orcid":false,"given":"Enrica","family":"Cerilli","sequence":"additional","affiliation":[{"name":"CIMeC\u2014Center for Mind\/Brain Sciences, University of Trento, Piazza della Manifattura 1, 38068 Rovereto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5750-8505","authenticated-orcid":false,"given":"Luigi","family":"Balasco","sequence":"additional","affiliation":[{"name":"CIMeC\u2014Center for Mind\/Brain Sciences, University of Trento, Piazza della Manifattura 1, 38068 Rovereto, Italy"},{"name":"Department of Life Sciences and Public Health, Universita\u2019 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6487-9478","authenticated-orcid":false,"given":"Ginevra Matilde","family":"Dall\u2019O\u2019","sequence":"additional","affiliation":[{"name":"CIMeC\u2014Center for Mind\/Brain Sciences, University of Trento, Piazza della Manifattura 1, 38068 Rovereto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Chelini","sequence":"additional","affiliation":[{"name":"CIMeC\u2014Center for Mind\/Brain Sciences, University of Trento, Piazza della Manifattura 1, 38068 Rovereto, Italy"},{"name":"CNR Neuroscience Institute, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0990-9419","authenticated-orcid":false,"given":"Anna","family":"Pastore","sequence":"additional","affiliation":[{"name":"Metabolomics and Proteomics Unit, \u2018Bambino Ges\u00f9\u2019 Children\u2019s Hospital, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7084-946X","authenticated-orcid":false,"given":"Birgit","family":"Weinberger","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Aging Research, University of Innsbruck, Rennweg 10, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1496-9889","authenticated-orcid":false,"given":"Yuri","family":"Bozzi","sequence":"additional","affiliation":[{"name":"CIMeC\u2014Center for Mind\/Brain Sciences, University of Trento, Piazza della Manifattura 1, 38068 Rovereto, Italy"},{"name":"CNR Neuroscience Institute, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Publishing. [5th ed.].","DOI":"10.1176\/appi.books.9780890425596"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1002\/aur.2696","article-title":"Global prevalence of autism: A systematic review update","volume":"15","author":"Zeidan","year":"2022","journal-title":"Autism Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41398-023-02374-w","article-title":"Comorbidities in autism spectrum disorder and their etiologies","volume":"13","author":"Khachadourian","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15585\/mmwr.ss7202a1","article-title":"Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years\u2014Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2020","volume":"72","author":"Maenner","year":"2023","journal-title":"MMWR. Surveill. Summ."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"281","DOI":"10.31887\/DCNS.2012.14.3\/pchaste","article-title":"Autism risk factors: Genes, environment, and gene-environment interactions","volume":"14","author":"Chaste","year":"2012","journal-title":"Dialog. Clin. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1038\/s41588-022-01104-0","article-title":"Rare coding variation provides insight into the genetic architecture and phenotypic context of autism","volume":"54","author":"Fu","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Pangrazzi, L., Balasco, L., and Bozzi, Y. (2020). Oxidative stress and immune system dysfunction in autism spectrum disorders. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093293"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.bbi.2010.08.003","article-title":"Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome","volume":"25","author":"Ashwood","year":"2011","journal-title":"Brain Behav. Immun."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"J\u00e1come, M.C.I., Chac\u00f2n, L.M.M., Cuesta, H.V., Rizo, C.M., Santiesteban, M.W., Hernandez, L.R., Garc\u00eda, E.N., Fraguela, M.E.G., Verdecia, C.I.F., and Hurtado, Y.V. (2016). Peripheral inflammatory markers contributing to comorbidities in autism. Behav. Sci., 6.","DOI":"10.3390\/bs6040029"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.jneuroim.2008.12.002","article-title":"Elevated immune response in the brain of autistic patients","volume":"207","author":"Li","year":"2009","journal-title":"J. Neuroimmunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/ana.20315","article-title":"Neuroglial activation and neuroinflammation in the brain of patients with autism","volume":"57","author":"Vargas","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Pangrazzi, L., Cerilli, E., Balasco, L., Tobia, C., Dall\u2019O\u2019, G.M., Chelini, G., Perini, S., Filosi, M., Ravizza, T., and Vezzani, A. (2023). The interplay between oxidative stress and inflammation supports autistic-related behaviors in mice. Biorxiv.","DOI":"10.1101\/2023.09.11.557109"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1002\/ajmg.b.30366","article-title":"Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism","volume":"141B","author":"James","year":"2006","journal-title":"Am. J. Med Genet. Part B Neuropsychiatr. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41398-020-01135-3","article-title":"Oxidative stress marker aberrations in children with autism spectrum disorder: A systematic review and meta-analysis of 87 studies (N = 9109)","volume":"11","author":"Chen","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e134","DOI":"10.1038\/tp.2012.61","article-title":"Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain","volume":"2","author":"Rose","year":"2012","journal-title":"Transl. Psychiatry"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Liu, X., Lin, J., Zhang, H., Khan, N.U., Zhang, J., Tang, X., Cao, X., and Shen, L. (2022). Oxidative stress in autism spectrum disorder\u2014Current progress of mechanisms and biomarkers. Front. Psychiatry, 13.","DOI":"10.3389\/fpsyt.2022.813304"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1177\/0004867420952540","article-title":"Effectiveness of N-acetylcysteine in autism spectrum disorders: A meta-analysis of randomized controlled trials","volume":"55","author":"Lee","year":"2021","journal-title":"Aust. N. Z. J. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nature09965","article-title":"Shank3 mutant mice display autistic-like behaviours and striatal dysfunction","volume":"472","author":"Feliciano","year":"2011","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3042","DOI":"10.1093\/cercor\/bhab399","article-title":"Abnormal Whisker-Dependent Behaviors and Altered Cortico-Hippocampal Connectivity in Shank3b\u2212\/\u2212 Mice","volume":"32","author":"Balasco","year":"2022","journal-title":"Cereb. Cortex"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1159\/000334260","article-title":"The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)","volume":"2","author":"Phelan","year":"2012","journal-title":"Mol. Syndr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"577870","DOI":"10.1016\/j.jneuroim.2022.577870","article-title":"Immune dysfunction in the cerebellum of mice lacking the autism candidate gene Engrailed 2","volume":"367","author":"Pangrazzi","year":"2022","journal-title":"J. Neuroimmunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1006\/nlme.1995.0002","article-title":"Role of preoperative and postoperative sensorimotor training on restoration of the equilibrium behavior in adult mice following cerebellectomy","volume":"64","author":"Caston","year":"1995","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/j.1601-1848.2004.00076.x","article-title":"Sociability and preference for social novelty in five inbred strains: An approach to assess autistic-like behavior in mice","volume":"3","author":"Moy","year":"2004","journal-title":"Genes Brain Behav."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1007\/s11695-021-05701-6","article-title":"Changes in total homocysteine and glutathione levels after laparoscopic sleeve gastrectomy in children with metabolic-associated fatty liver disease","volume":"32","author":"Pastore","year":"2021","journal-title":"Obes. Surg."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2944","DOI":"10.1111\/febs.14466","article-title":"A guide to chemokines and their receptors","volume":"285","author":"Hughes","year":"2018","journal-title":"FEBS J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2384","DOI":"10.4049\/jimmunol.1303240","article-title":"Matrix met-alloproteinase-8 plays a pivotal role in neuroinflammation by modulating TNF-\u03b1 activation","volume":"193","author":"Lee","year":"2014","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1111\/j.1474-9726.2012.00870.x","article-title":"Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response","volume":"11","author":"Jurk","year":"2012","journal-title":"Aging Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1073\/pnas.1318281111","article-title":"Characterization of the IL-15 niche in primary and secondary lymphoid organs in vivo","volume":"111","author":"Cui","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Meryk, A., Grasse, M., Balasco, L., Kapferer, W., Grubeck-Loebenstein, B., and Pangrazzi, L. (2020). Antioxidants N-Acetylcysteine and Vitamin C Improve T Cell Commitment to Memory and Long-Term Maintenance of Immunological Memory in Old Mice. Antioxidants, 9.","DOI":"10.3390\/antiox9111152"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"eade1283","DOI":"10.1126\/scitranslmed.ade1283","article-title":"A single-cell genomic atlas for matura-tion of the human cerebellum during early childhood","volume":"15","author":"Ament","year":"2023","journal-title":"Sci. Transl. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.cell.2011.08.040","article-title":"Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits","volume":"147","author":"Abrahams","year":"2011","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/2040-2392-5-30","article-title":"Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice","volume":"5","author":"Wang","year":"2014","journal-title":"Mol. Autism"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1002\/glia.22955","article-title":"CD14 is a key organizer of microglial responses to CNS infection and injury","volume":"64","author":"Janova","year":"2016","journal-title":"Glia"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0165-5728(02)00046-2","article-title":"Infiltrating CD14+ monocytes and expression of CD14 by activated parenchymal microglia\/macrophages contribute to the pool of CD14+ cells in ischemic brain lesions","volume":"126","author":"Beschorner","year":"2002","journal-title":"J. Neuroimmunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1742-2094-2-7","article-title":"Involvement of \u03b2-chemokines in the development of inflammatory demyelination","volume":"2","author":"Banisor","year":"2005","journal-title":"J. Neuroinflammation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5846","DOI":"10.1074\/jbc.272.9.5846","article-title":"Molecular cloning of a novel human CC chemokine liver and activation-regulated chemokine (LARC) expressed in liv-er. Chemotactic activity for lymphocytes and gene localization on chromosome 2","volume":"272","author":"Hieshima","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4892","DOI":"10.1182\/blood-2007-11-125039","article-title":"CCL5-mediated T-cell chemotaxis involves the initiation of mRNA translation through mTOR\/4E-BP1","volume":"111","author":"Murooka","year":"2008","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.cellimm.2011.05.001","article-title":"CCL5 induces a pro-inflammatory profile in microglia in vitro","volume":"270","author":"Sun","year":"2011","journal-title":"Cell. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nrm2125","article-title":"Matrix metalloproteinases and the regulation of tissue remodelling","volume":"8","author":"Ewald","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1111\/febs.15570","article-title":"A guide to assessing cellular senescence in vitro and in vivo","volume":"288","author":"Baker","year":"2021","journal-title":"FEBS J."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Lai, C.-C., Baskaran, R., Tsao, C.-Y., Tuan, L.-H., Siow, P.-F., Palani, M., Lee, L.J.-H., Liu, C.-M., Hwu, H.-G., and Lee, L.-J. (2022). Chronic N-Acetylcysteine Treatment Prevents Amphetamine-Induced Hyperactivity in Heterozygous Disc1 Mutant Mice, a Putative Prodromal Schizophrenia Animal Model. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23169419"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s13229-017-0142-z","article-title":"Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism","volume":"8","author":"Dhamne","year":"2017","journal-title":"Mol. Autism"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.3390\/ijms13022091","article-title":"Antioxidant-Induced Stress","volume":"13","author":"Villanueva","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_44","first-page":"45","article-title":"Antioxidative stress","volume":"5","author":"Aslan","year":"2000","journal-title":"East. J. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7789","DOI":"10.1073\/pnas.1403813111","article-title":"Glutathione-dependent and -independent oxidative stress-control mechanisms distinguish normal human mammary epithelial cell subsets","volume":"111","author":"Kannan","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"eaau6085","DOI":"10.1126\/sciimmunol.aau6085","article-title":"Structure and function of the immune system in the spleen","volume":"4","author":"Lewis","year":"2019","journal-title":"Sci. Immunol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/13\/11\/1390\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:32:25Z","timestamp":1760113945000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/13\/11\/1390"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,14]]},"references-count":46,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["antiox13111390"],"URL":"https:\/\/doi.org\/10.3390\/antiox13111390","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,14]]}}}