Title: Changes in Brain Connectivity Linked to Puberty Provide Insights into Autism and Schizophrenia Risk in Genetic Disorder
A pioneering study conducted by UCLA Health along with global partners has revealed significant alterations in brain connectivity that may explain why certain children with a rare genetic disorder have an elevated risk of developing neuropsychiatric disorders such as autism and schizophrenia. This investigation, published recently in Science Advances, centers around a genetic disorder known as chromosome 22q11.2 deletion syndrome, which results from missing DNA on chromosome 22.
Investigating the Brain’s Intricate Wiring
Developmental psychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia, are multifaceted conditions often characterized by interruptions in brain connectivity. However, pinpointing the biological origins of these interruptions has been challenging. By focusing on a genetically defined disorder, researchers aimed to isolate and examine specific neural mechanisms that may influence these psychiatric risks.
Chromosome 22q11.2 deletion syndrome serves as a crucial model because individuals with this condition are at a significantly heightened risk of developing autism or schizophrenia. Nevertheless, the biological connection between the missing genetic material and modified brain function had not been well understood until now.
Examining Both Humans and Mice
To uncover potential mechanisms, the research team utilized functional magnetic resonance imaging (fMRI) to assess brain function in both humans and genetically modified mice that replicate the condition. This cross-species methodology enabled researchers to identify shared patterns in brain changes throughout various stages of development.
One of the most notable discoveries was a considerable transition in brain connectivity around the onset of puberty. Prior to puberty, both human and mouse models with the deletion exhibited heightened connectivity in crucial brain regions, particularly those implicated in social behavior and prone to disruption in autism. However, after puberty, this pattern reversed: those same areas became less connected compared to individuals without the deletion.
“This shift from hyper- to hypo-connectivity illuminates the potential reasons certain psychiatric symptoms may materialize or escalate during adolescence, a vital phase for brain maturation,” stated co-senior author Dr. Carrie Bearden, a professor at the UCLA Semel Institute for Neuroscience and Human Behavior and the UCLA Brain Research Institute.
Synaptic Pruning and the Influence of GSK3-beta
Delving further into the brain’s cellular underpinnings, the researchers focused on dendritic spines — small protrusions on neurons that facilitate synaptic connections. In the genetically modified mice, younger specimens exhibited a greater number of dendritic spines than their non-altered (wild-type) peers. However, post-puberty, these mice encountered a marked decrease in dendritic spine density, indicating an excessive variant of synaptic pruning.
Synaptic pruning is a natural and essential process through which the brain eliminates weaker synaptic connections to enhance efficiency. However, excessive pruning can result in under-connectivity — a trait commonly seen in individuals with schizophrenia and sometimes in autism.
One potential factor is the protein GSK3-beta, which plays a role in regulating synaptic plasticity and pruning. When the researchers inhibited GSK3-beta activity with targeted drug therapy, they observed a temporary restoration of brain function and dendritic spine density in the mice. Furthermore, gene analysis of human subjects with the deletion indicated significant presence in regions linked to GSK3-beta regulation, suggesting a common biological pathway.
From Neural Connectivity to Behavioral Outcomes
In addition to neural transformations, the study also connected these connectivity alterations to shifts in behavior. In both humans and mice, the changes in connectivity following puberty were tied to indications of disrupted social behavior — commonly associated with autism spectrum disorder.
“These results imply that the excessive removal of synapses during development is not merely a structural concern but one that directly influences behavioral difficulties,” Dr. Bearden elaborated. “If we can address the underlying synaptic dysfunction during a pivotal window, we may have the potential to avert or lessen psychiatric symptoms.”
Significance and Future Prospects
This research presents a compelling biological model for understanding how particular genetic mutations can alter brain wiring over time, contributing to psychiatric conditions that surface primarily during adolescence. By highlighting GSK3-beta as a potential modulator of this mechanism, the study paves the way for innovative therapeutic approaches aimed at adjusting synaptic pruning in at-risk youth.
The implications extend beyond chromosome 22q11.2 deletion syndrome. As irregular synaptic pruning and functional connectivity are also observed in individuals without the deletion but with autism or schizophrenia, targeting pathways such as GSK3-beta could benefit a broader population.
The study was co-directed by Alessandro Gozzi from the Istituto Italiano di Tecnologia in Rovereto, Italy, exemplifying a cross-continental collaboration that merges fundamental science and clinical research.
As researchers continue to untangle the complex relationships between genetics, brain development, and behavior, these findings highlight the potential of targeted, translational research in advancing precision medicine — particularly for neurodevelopmental disorders that pose significant treatment and comprehension challenges.