22q11.2 Deletion Syndrome (22q11DS), a major risk factor schizophrenia and autism, is often associated with disrupted brain connectivity. However, the developmental and neural underpinnings of brain connectopathy in 22q11DS remain unclear. Using mouse fMRI, we found that 22q11DS-related dysconnectivity exhibits a stereotypical developmental trajectory, with widespread functional hyperconnectivity in pre-pubertal mice reverting to focal fronto-hippocampal hypoconnectivity in adulthood. Notably, juvenile hyperconnectivity, but not adult hypoconnectivity, was completely rescued by a GSK3β antagonist. Finally, guided by our mouse model data, we identified a similar developmental trajectory in 22q11DS patients, hence corroborating the translational validity of these findings.
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