{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:38:34Z","timestamp":1792460314484,"version":"4.5.0"},"reference-count":102,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T00:00:00Z","timestamp":1723593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["Ricerca corrente 2023"],"award-info":[{"award-number":["Ricerca corrente 2023"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["5X1000"],"award-info":[{"award-number":["5X1000"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition with several identified risk factors, both genetic and non-genetic. Among these, prenatal exposure to valproic acid (VPA) has been extensively associated with the development of the disorder. The zebrafish, a cost- and time-effective model, is useful for studying ASD features. Using validated VPA-induced ASD zebrafish models, we aimed to provide new insights into VPA exposure effects during embryonic development and to identify new potential biomarkers associated with ASD-like features. Dose\u2013response analyses were performed in vivo to study larval phenotypes and mechanisms underlying neuroinflammation, mitochondrial dysfunction, oxidative stress, microglial cell status, and motor behaviour. Wild-type and transgenic Tg(mpeg1:EGFP) zebrafish were water-exposed to VPA doses (5 to 500 \u00b5M) from 6 to 120 h post-fertilisation (hpf). Embryos and larvae were monitored daily to assess survival and hatching rates, and numerous analyses and tests were conducted from 24 to 120 hpf. VPA doses higher than 50 \u00b5M worsened survival and hatching rates, while doses of 25 \u00b5M or more altered morphology, microglial status, and larval behaviours. VPA 50 \u00b5M also affected mRNA expression of inflammatory cytokines and neurogenesis-related genes, mitochondrial respiration, and reactive oxygen species accumulation. The study confirmed that VPA alters brain homeostasis, synaptic interconnections, and neurogenesis-related signalling pathways, contributing to ASD aetiopathogenesis. Further studies are essential to identify novel ASD biomarkers for developing new drug targets and tailored therapeutic interventions for ASD.<\/jats:p>","DOI":"10.3390\/cells13161349","type":"journal-article","created":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T05:23:27Z","timestamp":1723613007000},"page":"1349","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Delving into the Complexity of Valproate-Induced Autism Spectrum Disorder: The Use of Zebrafish Models"],"prefix":"10.3390","volume":"13","author":[{"given":"Diletta","family":"Camussi","sequence":"first","affiliation":[{"name":"Department of Neurobiology and Molecular Medicine, IRCCS Stella Maris Foundation, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4941-635X","authenticated-orcid":false,"given":"Valentina","family":"Naef","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Molecular Medicine, IRCCS Stella Maris Foundation, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3474-9266","authenticated-orcid":false,"given":"Letizia","family":"Brogi","sequence":"additional","affiliation":[{"name":"Bio@SNS, Department of Neurosciences, Scuola Normale Superiore, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Della Vecchia","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Molecular Medicine, IRCCS Stella Maris Foundation, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0194-0702","authenticated-orcid":false,"given":"Maria","family":"Marchese","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Molecular Medicine, IRCCS Stella Maris Foundation, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferdinando","family":"Nicoletti","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Vittorio Erspamer, \u201cLa Sapienza\u201d University of Rome, 00185 Rome, Italy"},{"name":"IRCSS Neuromed, \u201cLa Sapienza\u201d University of Rome, 86077 Pozzilli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo M.","family":"Santorelli","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Molecular Medicine, IRCCS Stella Maris Foundation, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4879-6610","authenticated-orcid":false,"given":"Rosario","family":"Licitra","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Molecular Medicine, IRCCS Stella Maris Foundation, 56128 Pisa, Italy"},{"name":"Department of Veterinary Sciences, University of Pisa, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2013). 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