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Thus, searching for novel and effective drugs ameliorating core symptoms, in particular social deficits, is of utmost importance. Duloxetine (DLX), an antidepressant that has been identified as an agonist mimetic for the cell adhesion molecule L1, exhibits beneficial functions in vitro and in vivo. Therefore, in this study, we focused on the rapid and persistent neuroprotective function of DLX following valproic acid (VPA)\u2010triggered hyperactivity, anxiety\u2010like behavior and social deficits in zebrafish. Embryonic exposure to VPA reduced survival in a dose\u2010 and time\u2010dependent manner, delayed hatching, and also resulted in a significant number of malformed larvae. After initial dose\u2013response experiments in zebrafish larvae, 10\u00a0\u03bcM VPA exposure between 0.33 and 4.5\u2009days post fertilization (dpf) was identified as an effective concentration that led to an early and persistent ASD\u2010like phenotype in zebrafish. ASD\u2010like elevated acetylcholine esterase (AChE) activity and reduced Akt\u2013mTOR signaling was observed in zebrafish whole brain. Acute administration of DLX (4.5\u20136 dpf) reduced the VPA\u2010induced ASD\u2010like phenotype in zebrafish larvae. Additionally, such early\u2010life acute DLX treatment had long\u2010term effects in ameliorating social impairments, hyperactivity, and anxiety\u2010like behaviors through adulthood. This was accompanied by reduced AChE activity and by normalized Akt\u2013mTOR signaling. Overall, DLX treatment showed a long\u2010term therapeutic effect on autistic\u2010like behaviors, and alteration of AChE activity and Akt\u2013mTOR signaling were identified as crucial in the VPA\u2010induced ASD zebrafish model.<\/jats:p>","DOI":"10.1002\/aur.2620","type":"journal-article","created":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T18:11:24Z","timestamp":1633457484000},"page":"27-41","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Duloxetine ameliorates valproic<scp>acid\u2010induced<\/scp>hyperactivity, anxiety\u2010like behavior, and social interaction deficits in zebrafish"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2337-0544","authenticated-orcid":false,"given":"Thomson Patrick","family":"Joseph","sequence":"first","affiliation":[{"name":"Center of Neuroscience Shantou University Medical College Shantou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center of Neuroscience Shantou University Medical College Shantou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu Yang","family":"Sai","sequence":"additional","affiliation":[{"name":"Center of Neuroscience Shantou University Medical College Shantou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Center of Neuroscience Shantou University Medical College Shantou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley Li","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Cell Biology Shantou University Medical College Shantou China"},{"name":"Guangdong Provincial Key Laboratory for Breast Cancer Diagnosis and Treatment Shantou University Medical College Shantou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melitta","family":"Schachner","sequence":"additional","affiliation":[{"name":"Center of Neuroscience Shantou University Medical College Shantou China"},{"name":"Department of Cell Biology and Neuroscience, Keck Center for Collaborative Neuroscience Rutgers The State University of New Jersey Piscataway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,10,3]]},"reference":[{"key":"e_1_2_12_2_1","unstructured":"Ahn Y. 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