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Depletion of the adult neural stem\/progenitor cell (NSPCs) pool and neurogenic decline have been recently described in mice expressing synaptic susceptibility genes associated with autism spectrum disorder (ASDs). To gain further insight into mechanisms regulating neurogenesis in mice carrying mutations in synaptic genes related to monogenic ASDs, we used the R451C Neuroligin3 knock\u2010in (Nlgn3 KI) mouse, which is characterized by structural brain abnormalities, deficits in synaptic functions and reduced sociability. We show that the number of adult\u2010born neurons, but not the size of the NSPC pool, was reduced in the ventral dentate gyrus in knock\u2010in mice. Notably, this neurogenic decline was rescued by daily injecting mice with 10\u00a0mg\/Kg of the antidepressant fluoxetine for 20\u2009consecutive days. Sustained treatment also improved KI mice's sociability and increased the number of c\u2010Fos active adult\u2010born neurons, compared with vehicle\u2010injected KI mice. Our study uncovers neurogenesis\u2010mediated alterations in the brain of R451C KI mouse, showing that the R451C Nlgn3 mutation leads to lasting, albeit pharmacologically reversible, changes in the brain, affecting neuron formation in the adult hippocampus. Our results suggest that fluoxetine can ameliorate social behaviour in KI mice, at least in part, by rescuing adult hippocampal neurogenesis, which may be relevant for the pharmacological treatment of ASDs.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15753-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15753","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T07:33:36Z","timestamp":1672385616000},"page":"318-333","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Adult hippocampal neurogenesis and social behavioural deficits in the <scp>R451C<\/scp> Neuroligin3 mouse model of autism are reverted by the antidepressant fluoxetine"],"prefix":"10.1111","volume":"165","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6365-1332","authenticated-orcid":false,"given":"Roberta","family":"Gioia","sequence":"first","affiliation":[{"name":"Department of Biology and Biotechnology \u201cCharles Darwin\u201d, Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Seri","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u201cCharles Darwin\u201d, Sapienza University of Rome  Rome Italy"},{"name":"PhD program in Behavioral Neuroscience Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Diamanti","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u201cCharles Darwin\u201d, Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Fimman\u00f2","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u201cCharles Darwin\u201d, Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Vitale","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u201cCharles Darwin\u201d, Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8958-6148","authenticated-orcid":false,"given":"Henrik","family":"Ahlenius","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Clinical Sciences Lund, Neurology, Stem Cells, Aging and Neurodegeneration Lund University  Lund Sweden"},{"name":"Lund Stem Cell Center  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaal","family":"Kokaia","sequence":"additional","affiliation":[{"name":"Lund Stem Cell Center, Department of Clinical Sciences Lund University Hospital  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felice","family":"Tirone","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology National Research Council  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Micheli","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology National Research Council  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Biagioni","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u201cCharles Darwin\u201d, Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Lupo","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u201cCharles Darwin\u201d, Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Rinaldi","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u201cCharles Darwin\u201d, Sapienza University of Rome  Rome Italy"},{"name":"Centre for Research in Neurobiology \u201cD. 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