Divergent transcriptomic pathways underlie sex-biased cognitive rescue by developmental GSK3B inhibition in a mouse model of 22q11.2 deletion syndrome

Abstract Neuropsychiatric disorders such as schizophrenia frequently exhibit marked sex differences in onset, clinical features, and treatment response. 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 Df(16)A +/− 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)–ventral hippocampus (vHPC) theta synchrony in male Df(16)A +/− 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, Gsk3b expression itself displayed opposing patterns in Df(16)A +/− 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’s 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.