A groundbreaking study from UCLA Health has uncovered significant changes in brain connectivity among individuals with chromosome 22q11.2 deletion syndrome, offering potential explanations for the increased risk of autism and schizophrenia in affected children. By employing advanced imaging techniques on both human subjects and genetically engineered mice, researchers identified a reversal in neural connections—hyperconnectivity before puberty transitioning to under-connectivity afterward. This shift is closely associated with alterations in synaptic structure, particularly a dramatic reduction in dendritic spines post-puberty. The findings also highlight the role of the protein GSK3-beta, suggesting it as a promising therapeutic target for neurodevelopmental disorders.
Chromosome 22q11.2 deletion syndrome, caused by missing DNA segments on chromosome 22, is linked to heightened risks of neuropsychiatric conditions such as autism and schizophrenia. To explore this connection further, researchers utilized functional brain imaging technology across species. In juvenile mice modified to mimic the genetic condition, there was an observed increase in dendritic spine density compared to normal mice. However, once these mice reached puberty, their spine density significantly dropped. Professor Carrie Bearden from UCLA explained that these synaptic differences might clarify why psychiatric disorders often exhibit altered functional connectivity patterns seen in MRI scans.
Further investigation revealed that inhibiting GSK3-beta could temporarily restore both brain activity and dendritic spine density in the genetically modified mice. This restoration suggests the protein plays a crucial role in regulating synapse removal. Additionally, human participants with the same genetic condition showed similar brain connectivity changes affecting regions rich in genes related to GSK3-beta. These areas are also tied to autism-relevant transcripts, indicating that altered wiring contributes to autism traits.
According to Bearden, the study's findings strongly imply that excessive pruning of synapses during development may be responsible for the behavioral challenges observed in individuals with chromosome 22q11.2 deletion syndrome. Such synaptic dysfunction presents a potential avenue for interventions aimed at preventing or alleviating symptoms. Collaborating with Alessandro Gozzi from the Italian Institute of Technology, the team’s work underscores the importance of understanding synaptic mechanisms in developmental brain dysconnectivity.
The implications of this research extend beyond understanding specific genetic syndromes. It provides critical insights into broader neurodevelopmental disorders, opening doors to new treatments targeting synaptic regulation. By linking changes in brain connectivity to synaptic alterations and identifying GSK3-beta as a pivotal player, the study paves the way for innovative therapeutic strategies addressing autism and schizophrenia.
