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

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Chromosome 22q11.2 deletion syndrome (22q11DS) is linked to increased risk for neuropsychiatric disorders, including autism and schizophrenia.
• While brain dysconnectivity is reported in 22q11DS, its underlying biological mechanisms and developmental course are not fully understood.

Purpose of the Study:

• To investigate the developmental trajectory and neural basis of brain dysconnectivity in 22q11DS using a cross-species approach.
• To identify potential synaptic mechanisms and therapeutic targets for 22q11DS-associated neurodevelopmental alterations.

Main Methods:

• Utilized LgDel mice, a model for 22q11DS, and human patient data.
• Employed functional magnetic resonance imaging (fMRI) to assess brain connectivity across different ages.
• Examined dendritic spine density and investigated the effects of GSK3β inhibition.

Main Results:

• Observed age-specific brain dysconnectivity patterns in LgDel mice, transitioning from hyperconnectivity to hypoconnectivity during puberty.
• Found that these connectivity changes correlated with altered dendritic spine density and were normalized by GSK3β inhibition.
• Identified analogous pubertal connectivity shifts in human 22q11DS, particularly in cortical regions associated with GSK3β and autism-related genes, predicting social deficits.

Conclusions:

• Synaptic mechanisms are implicated in the developmental brain dysconnectivity observed in 22q11DS.
• GSK3β inhibition shows potential for normalizing synaptic and connectivity alterations in 22q11DS.
• The findings highlight a conserved cross-species developmental trajectory of brain dysconnectivity in 22q11DS, offering insights into its neurobiological underpinnings and potential interventions.