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Here, we investigated the role of PDE2A in ASD pathogenesis using two rat models that reflect one of either the genetic or environmental factors involved in the human disease: the genetic <jats:italic>Fmr1-<\/jats:italic><jats:sup><jats:italic>\u0394<\/jats:italic><\/jats:sup><jats:italic>exon 8<\/jats:italic> rat model and the environmental rat model based on prenatal exposure to valproic acid (VPA, 500\u2009mg\/kg). Prior to behavioral testing, the offspring was treated with the PDE2A inhibitor BAY607550 (0.05\u2009mg\/kg at infancy, 0.1\u2009mg\/kg at adolescence and adulthood). Socio-communicative symptoms were assessed in both models through the ultrasonic vocalization test at infancy and three-chamber test at adolescence and adulthood, while cognitive impairments were assessed by the novel object recognition test in <jats:italic>Fmr1-<\/jats:italic><jats:sup><jats:italic>\u0394<\/jats:italic><\/jats:sup><jats:italic>exon 8<\/jats:italic> rats (adolescence and adulthood) and by the inhibitory avoidance test in VPA-exposed rats (adulthood). PDE2A enzymatic activity in VPA-exposed infant rats was also assessed. In line with the increased PDE2A enzymatic activity previously observed in the brain of <jats:italic>Fmr1<\/jats:italic>-KO animals, we found an altered upstream regulation of PDE2A activity in the brain of VPA-exposed rats at an early developmental age (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Pharmacological inhibition of PDE2A normalized the communicative (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), social (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), and cognitive impairment (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) displayed by both <jats:italic>Fmr1-<\/jats:italic><jats:sup><jats:italic>\u0394<\/jats:italic><\/jats:sup><jats:italic>exon 8<\/jats:italic> and VPA-exposed rats. Altogether, these data highlight a key role of PDE2A in brain development and point to PDE2A inhibition as a promising pharmacological approach for the deficits common to both FXS and ASD.<\/jats:p>","DOI":"10.1038\/s41398-022-01885-2","type":"journal-article","created":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T10:03:15Z","timestamp":1648202595000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Phosphodiesterase 2A inhibition corrects the aberrant behavioral traits observed in genetic and environmental preclinical models of Autism Spectrum Disorder"],"prefix":"10.1038","volume":"12","author":[{"given":"Sara","family":"Schiavi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Carbone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Melancia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"di Masi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marielle","family":"Jarjat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9deric","family":"Brau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Cardarelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Giorgi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6411-1517","authenticated-orcid":false,"given":"Barbara","family":"Bardoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3922-6045","authenticated-orcid":false,"given":"Viviana","family":"Trezza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,25]]},"reference":[{"key":"1885_CR1","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association. 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