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Maternal use of valproic acid (VPA) during pregnancy is associated with an increased risk of ASD in offspring. The prevailing pathophysiological hypothesis for ASD involves excitation\/inhibition (E\/I) imbalances and serotonergic dysfunction. Here, we investigated the association between glutamatergic-serotonergic neuronal interactions and ASD-like behaviors in mice exposed to prenatal VPA. Prenatal VPA exposure induced excessive repetitive self-grooming behavior and impaired social behavior and object recognition memory in young adult period. Prenatal VPA mice showed hyper-glutamatergic function (increase in basal extracellular glutamate levels and CaMKII phosphorylation) and hypo-serotonergic function (decrease in 5-hydroxyindoleacetic acid and stimulation-induced serotonin [5-HT] release, but an increase in 5-HT transporter expression) in the prefrontal cortex. Treatment with a low-affinity NMDA receptor antagonist (memantine), a selective 5-HT reuptake inhibitor (fluoxetine), and a 5-HT\n                    <jats:sub>1A<\/jats:sub>\n                    receptor agonist (tandospirone) attenuated both the increase in CaMKII phosphorylation and ASD-like behavior of prenatal VPA mice. Opto-genetic activation of the serotonergic neuronal system attenuated impairments in social behavior and object recognition memory in prenatal VPA mice. WAY-100635\u2014a 5-HT\n                    <jats:sub>1A<\/jats:sub>\n                    receptor antagonist\u2014antagonized the effect of fluoxetine on impaired social behavior and object recognition memory. These results suggest that E\/I imbalance and ASD-like behavior are associated with hypo-serotonergic receptor signaling through 5-HT\n                    <jats:sub>1A<\/jats:sub>\n                    receptors in prenatal VPA mice.\n                  <\/jats:p>","DOI":"10.1038\/s41386-024-02004-z","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T10:01:46Z","timestamp":1728640906000},"page":"739-750","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Autism spectrum disorder-like behaviors induced by hyper-glutamatergic NMDA receptor signaling through hypo-serotonergic 5-HT1A receptor signaling in the prefrontal cortex in mice exposed to prenatal valproic acid"],"prefix":"10.1038","volume":"50","author":[{"given":"Hitomi","family":"Kurahashi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuo","family":"Kunisawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2511-0057","authenticated-orcid":false,"given":"Kenji F.","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisayoshi","family":"Kubota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaya","family":"Hasegawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai","family":"Miyachi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Moriya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoichi","family":"Hasegawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5050-7748","authenticated-orcid":false,"given":"Taku","family":"Nagai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuniaki","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshitaka","family":"Nabeshima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3833-4041","authenticated-orcid":false,"given":"Akihiro","family":"Mouri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,11]]},"reference":[{"key":"2004_CR1","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association, Diagnostic and statistical manual of mental disorders 5: Dsm-5 (2013).","DOI":"10.1176\/appi.books.9780890425596"},{"key":"2004_CR2","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1176\/appi.ajp.2011.10101532","volume":"168","author":"YS Kim","year":"2011","unstructured":"Kim YS, Leventhal BL, Koh YJ, Fombonne E, Laska E, Lim EC, et al. 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