Synaptic-dependent developmental dysconnectivity in 22q11.2 deletion syndrome
Chromosome 22q11.2 deletion increases the risk of neuropsychiatric disorders like autism and schizophrenia. Disruption of large-scale functional connectivity in 22q11 deletion syndrome (22q11DS) has been widely reported, but the biological factors driving these changes remain unclear. We used a cross-species design to uncover the developmental trajectory and neural underpinnings of brain dysconnectivity in 22q11DS. In LgDel mice, a model for 22q11DS, we found age-specific patterns of brain dysconnectivity, with widespread fMRI hyperconnectivity in juvenile mice reconfiguring to hippocampal hypoconnectivity over puberty. These changes correlated with developmental alterations in dendritic spine density, and both were transiently normalized by GSK3β inhibition, suggesting a synaptic origin for this phenomenon. Notably, analogous pubertal hyperconnectivity-to-hypoconnectivity reconfiguration occurs in human 22q11DS, affecting cortical regions enriched for GSK3β-associated synaptic genes and autism-relevant transcripts. This dysconnectivity also predicts age-dependent social alterations in 22q11DS individuals. These results suggest that synaptic mechanisms underlie developmental brain dysconnectivity in 22q11DS.
Authors
- Alexia Stuefer (ORCID: https://orcid.org/0000-0003-1630-6066)
- Caterina Montani (ORCID: https://orcid.org/0000-0002-3150-0302)
- A. Elizabeth de Guzman (ORCID: https://orcid.org/0000-0001-6675-4014)
- Filomena Grazia Alvino
- Carrie E. Bearden (ORCID: https://orcid.org/0000-0002-8516-923X)
- Charles Schleifer (ORCID: https://orcid.org/0000-0001-8411-0968)
- Wendy R. Kates (ORCID: https://orcid.org/0000-0003-3358-2572)
- Alberto Galbusera (ORCID: https://orcid.org/0000-0001-7213-0013)
- Leila Kushan (ORCID: https://orcid.org/0000-0002-2650-7147)
- Massimo Pasqualetti (ORCID: https://orcid.org/0000-0002-0844-8139)
- Declan Murphy (ORCID: https://orcid.org/0000-0002-6664-7451)
- Silvia Gini (ORCID: https://orcid.org/0009-0001-2757-3306)
- Noemi Barsotti (ORCID: https://orcid.org/0000-0002-6399-436X)
- Marco Pagani (ORCID: https://orcid.org/0000-0002-6052-6931)
- Alessandro Gozzi (ORCID: https://orcid.org/0000-0002-5731-4137)
- Francesco Papaleo (ORCID: https://orcid.org/0000-0002-6326-0657)
- Michael Lombardo (ORCID: https://orcid.org/0000-0001-6780-8619)
- David Sastre-Yagüe (ORCID: https://orcid.org/0000-0001-5901-6144)
- Antea Minetti (ORCID: https://orcid.org/0009-0009-2308-6330)
Institutions
- University of Pisa (IT)
- IMT School for Advanced Studies Lucca (IT)
- University of California, Los Angeles (US)
- King's College London (GB)
- University of Trento (IT)
- SUNY Upstate Medical University (US)
- Italian Institute of Technology (IT)
- Center for Neuroscience and Cognitive Systems (IT)
- Ospedale Policlinico San Martino (IT)
Publication Details
- Journal
- Science Advances
- Published
- 2025-03-12
- DOI
- https://doi.org/10.1126/sciadv.adq2807
- Citations
- 14
- Primary Topic
- Congenital heart defects research
- Type
- article
- Field-Weighted Citation Impact
- 10.48