Synaptic-dependent developmental dysconnectivity in 22q11.2 deletion syndrome

• DOI: 10.1126/sciadv.adq2807
• Publication Date: 2025-03-12T17:58:57Z
• Authors: Filomena Grazia A...; Silvia Gini; Antea Minetti; Marco Pagani; David Sastre-Yagüe; Noemi Barsotti; Elizabeth De Guzman; Charles Schleifer; Alexia Stuefer; Leila Kushan; Caterina Montani; Alberto Galbusera; Francesco Papaleo; Wendy R. Kates; Declan Murphy; Michael Vincent L...; Massimo Pasqualetti; Carrie E. Bearden; Alessandro Gozzi

Chromosome 22q11.2 deletion increases the risk of neuropsychiatric disorders like autism and schizophrenia. Disruption large-scale functional connectivity in 22q11 syndrome (22q11DS) has been widely reported, but biological factors driving these changes remain unclear. We used a cross-species design to uncover developmental trajectory neural underpinnings brain dysconnectivity 22q11DS. In LgDel mice, model for 22q11DS, we found age-specific patterns dysconnectivity, with widespread fMRI hyperconnectivity juvenile mice reconfiguring hippocampal hypoconnectivity over puberty. These correlated alterations dendritic spine density, both were transiently normalized by GSK3β inhibition, suggesting synaptic origin this phenomenon. Notably, analogous pubertal hyperconnectivity-to-hypoconnectivity reconfiguration occurs human affecting cortical regions enriched GSK3β-associated genes autism-relevant transcripts. This also predicts age-dependent social 22q11DS individuals. results suggest that mechanisms underlie