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However, the molecular and developmental bases of these differences remain poorly defined. Here, we report a sex-dependent effect of developmental, paralog-selective GSK3B inhibition on working memory (WM) in the\n                    <jats:italic>Df(16)A<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    mouse model of 22q11.2 deletion syndrome (22q11.2DS), a genetic condition conferring high risk for schizophrenia. Pharmacological inhibition of GSK3B with BRD3731 rescued WM deficits and enhanced prefrontal cortex (PFC)\u2013ventral hippocampus (vHPC) theta synchrony in male\n                    <jats:italic>Df(16)A<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    mice, but had no benefit in female mutants and impaired performance in wild-type (WT) females. Transcriptomic profiling of the postnatal PFC revealed previously unrecognized sex-by-genotype interactions in gene expression associated with the 22q11.2 deletion also implicating GSK3B-associated pathways. Notably,\n                    <jats:italic>Gsk3b<\/jats:italic>\n                    expression itself displayed opposing patterns in\n                    <jats:italic>Df(16)A<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    mice relative to WT mice, being elevated in males and reduced in females, potentially explaining the observed sex-specific behavioral and circuit responses. Our findings suggest that GSK3B is part of a broader, sexually dimorphic gene network that governs PFC circuit maturation and cognitive function. Specifically, our transcriptomic profiling delineates a postnatal window where the 22q11.2DS model exhibits these sexually dimorphic signatures. Notably, these signatures include many genes previously implicated in schizophrenia, autism, and intellectual disability, likely shaping the disorder\u2019s sex-specific pathophysiology. More broadly, this work underscores the importance of incorporating sex as a biological variable in translational research and supports precision psychiatry approaches that align interventions with sex-specific neurobiological profiles.\n                  <\/jats:p>","DOI":"10.1038\/s41398-026-04108-0","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T05:33:00Z","timestamp":1781155980000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Divergent transcriptomic pathways underlie sex-biased cognitive rescue by developmental GSK3B inhibition in a mouse model of 22q11.2 deletion syndrome"],"prefix":"10.1038","volume":"16","author":[{"given":"Johannes","family":"Passecker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5912-9234","authenticated-orcid":false,"given":"Chia-Yuan","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Dagunts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe M.","family":"Aloimonos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Leitner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arsenii","family":"Petryk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence F.","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxym V.","family":"Myroshnychenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Kupferschmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7491-4476","authenticated-orcid":false,"given":"Joseph A.","family":"Gogos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5488-8266","authenticated-orcid":false,"given":"Joshua A.","family":"Gordon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"4108_CR1","doi-asserted-by":"publisher","first-page":"417","DOI":"10.3109\/09540261.2010.515205","volume":"22","author":"KM Abel","year":"2010","unstructured":"Abel KM, Drake R, Goldstein JM. 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