Summary: Researchers have identified changes in brain connectivity before and after puberty that may explain why some children with chromosome 22q11.2 deletion syndrome are more susceptible to autism and schizophrenia. Using brain imaging in both mice and humans, the study found that brain regions involved in social behavior were hyperconnected in childhood but under-connected after puberty.
These shifts appear linked to changes in synaptic structure, particularly a sharp loss of dendritic spines after puberty. Inhibiting a key protein, GSK3-beta, partially restored connectivity in mice, highlighting a potential therapeutic target for neurodevelopmental disorders.
Key Facts:
- Connectivity Flip: Brain regions in 22q deletion were overconnected before puberty, under-connected after.
- Synaptic Link: Post-pubertal drop in dendritic spines correlated with disrupted social behaviors.
- Targetable Pathway: Inhibiting GSK3-beta restored connectivity and spine density in mice.
Source: UCLA
Changes in brain connectivity before and after puberty may explain why some children with a rare genetic disorder have higher risk of developing autism or schizophrenia, according to a UCLA Health study.
Developmental psychiatric disorders like autism and schizophrenia are associated with changes in brain functional connectivity. However, the complexity of these conditions make it difficult to understand the underlying biological causes.
By studying genetically defined brain disorders, researchers at UCLA Health and collaborators have shed light on possible mechanisms. “
The UCLA study examined a particular genetic condition called chromosome 22q11.2 deletion syndrome — caused by missing DNA on chromosome 22 — which is associated with higher risk of developing neuropsychiatric conditions such as autism and schizophrenia.
But the underlying biological basis of this association has not been well understood.
In the study recently published in the journal Science Advances, researchers used functional brain imaging in both mice and humans to investigate potential mechanisms driving the connection between the genetic mutation and development of neuropsychiatric conditions.
Functional brain imaging showed the brain regions in both humans and genetically modified mice were hyperconnected before puberty before switching to being under-connected after puberty, particularly in brain regions tied to social skills and autism.
Co-senior author Carrie Bearden, Professor at the UCLA Health Semel Institute and the UCLA Brain Research Institute, said changes at the synapse level appear to explain the sudden shift in connectivity and associated effects on social behavior
“Differences in functional connectivity observed on MRI are commonly found in psychiatric disorders, but we don’t have a good understanding of why. It was really valuable to study this phenomenon across species,” Bearden said.
Using mice that were genetically modified to mimic chromosome 22q11.2 deletion syndrome, Bearden and her colleagues at the Italian Institute of Technology found younger mice had a larger density of dendritic spines — small protrusions on brain cells used to communicate with other neurons via synapses — during childhood compared to wild-type (normal) mice.
After the mice reached the equivalent of puberty, the number of dendritic spines sharply decreased compared to wild-type mice.
The protein GSK3-beta, which is involved in synapse regulation, may play a role in the connectivity changes.
Bearden and her collaborators used a drug to inhibit GSK3-beta, which worked to temporarily restore brain activity and dendritic spine density in the mice, possibly by regulating the removal of dendritic spines.
Brain imaging of humans with the condition also found the brain regions affected by the connectivity changes had enriched genes related to GSK3-beta. Further, the brain connectivity changes were related to social behavior in humans, suggesting that the altered wiring contributes to autism traits.
These findings, Bearden said, suggests that synaptic dysfunction drives the changes in brain activity and could be a target to prevent or reduce symptoms caused by chromosome 22q11.2 deletion syndrome.
“These findings strongly suggest that over-weeding of synapses during development may contribute to the behavioral challenges we see,” Bearden said.
The study was co-led by Alessandro Gozzi of the Istituto Italiano di Tecnologia in Rovereto, Italy.
About this autism research news
Author: Will Houston
Source: UCLA
Contact: Will Houston – UCLA
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Synaptic-dependent developmental dysconnectivity in 22q11.2 deletion syndrome” by Carrie Bearden et al. Science Advances
Abstract
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.
